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International > Living, Studying & Working in New Zealand > About Invercargill City & the Southland Region
The Southland Region & Invercargill City
Southland is a large region with a low population density. The regional economy is fueled by primary industries such as farming, fishing and forestry. The major population centers are Invercargill, with a population of 51,696 (Census 2013) and Gore, which has a population of 12,033 (Census 2013). Invercargill is New Zealand's southernmost city, and the regional captial, however there are numerous townships spread throughout the region, ranging in size from thousands of residents, to places with resident populations in single figures.
A unique feature of Southland's climate is our long summer nights: we enjoy more daylight hours than any other part of the country. At the summer solstice, we have nearly 16 hours of daylight. On a dark, clear night, you may be able to witness the world famous Aurora Australis (Southern Lights). This magical atmospheric condition is like a spectacular light show in the night sky and results when particles from the sun interact with the earth's magnetic field. The resulting electric charge makes the gases in the atmosphere glow red, yellow and green.
Southland is a nature-lovers paradise, as the region contains the world-famous UNESCO World Heritage site of Milford Sound, Fiordland National Park, Stewart Island/Rakiura National Park, and the rugged Catlins. Activities such as skiing and snowboarding, mountain biking, jet boating, surfing, tramping (hiking), kayaking and more, are all available in multiple locations about the region, most within minutes of Invercargill city, and the most remote locations being no more than two hours journey by car.
Welcome to Invercargill City
Invercargill, Southland's capital, is a flat and spacious city situated just minutes from the coast; Oreti Beach is just ten minutes drive from SIT. It's a compact city and it is easy to find your way around to enjoy the excellent shopping, lively cafes, restaurants and bars, cultural attractions and outstanding nature reserves and parks.
Sport is a major theme for the city and we have an abundance of sports facilities, including an indoor stadium and cycling velodrome, Olympic size pool and countless parks and sport grounds. Our major recreational area, Sandy Point, is 2,000+ hectares of recreational land, and caters for both casual and organised recreation, including walking and running trails, mountain bike trails, horse riding, dog sledding, rowing, water skiing, motorcross, motor racing and speedway, field sports, and much more.
The city itself is home to a wide range of heritage and cultural facilities, including the Civic Theatre, Museum and Art Gallery and Queens Park. The variety and number of heritage buildings in the city centre add to Invercargill's character.
Known as the 'City of Water and Light' due to long summer daylight hours, glorious twilights and the abundance of our most important natural resource - water, the city reflects the importance of the farming sector it supports. Based on primary produce, Invercargill is critical in supporting the booming dairy industry, which in turn drives our renowned engineering sector to increasing levels of innovation and excellence.
Accommodation and living costs in Invercargill are considerably lower than in other major cities in New Zealand due to the abundance of available land for housing and gentle landforms, meaning relative ease of housing and infrastructure construction.
Invercargill is favourably placed on the Southern Scenic Route and is the gateway to some of New Zealand's most beautiful scenery and destinations, including the Southland heartland, Stewart Island, Queenstown, Fiordland and the Catlins.
The people of the City of Invercargill warmly invite you to come join us to experience the friendliness and hospitality that makes our city such a great place to live.
Event central
Living in Southland brings a wealth of lifestyle opportunities, including the many flagship events that are held each year.
The Burt Munro Challenge is a motorcycle rally of international acclaim. Held over four days in February each year, the event celebrates Invercargill's own world land-speed record holder, Burt Munro, and his 'World's Fastest Indian' motorcycle.
The world famous Bluff Oyster Festival is a chance to taste some of the freshest oysters plucked out of the ocean before they are exported around the world.
Shakespeare in the Park is held in Invercargill's Queens Park. This annual festival showcases some of Shakespeare's best works in an accessible, interactive, outdoor environment.
The Southland Festival of the Arts showcases outstanding imported and local arts activities in a range of genres: theatre, music, dance, literary arts and galleries.
The annual Tour of Southland captivates the country as road cyclists from around the world participate in this six-day stage race right across Southland.
Buskers from around the world descend on Invercargill for the annual Southland Busker's Festival, which unleashes several days of humorous hi-jinks. You can't miss it!
The International Food Festival offers the opportunity to tantalise your taste buds with food and entertainment from around the world.
Run, walk or bike the 12 kilometre Surf to City fun race, which starts from Oreti Beach and ends up in the centre of the city at Queens Park.
There is a wealth of other activities held during the year, including international and national sports competitions, the Royal New Zealand Ballet, the New Zealand Symphony Orchestra, a number of shows and performances and popular New Zealand bands and singers. You can find out what other events are going on at https://greatsouth.nz or take a look at the Friendly's 101 List https://www.youtube.com/watch?v=7hDV_fm4mP8 for plenty of free and low cost things to do in and around Invercargill.
Kia ora, Hello!
On behalf of the City of Invercargill, welcome to the Southern Institute of Technology.
SIT is the pride of Southland. As a Government Tertiary Institution it is committed to quality education, and I encourage you to make SIT your choice for higher education. SIT provides a dynamic, innovative and friendly environment for domestic and international students alike.
While studying with us, you will be able to enjoy Southland, New Zealand's most picturesque region. We live in a region full of adventure and recreational opportunities through to extreme sports challenges. Not only will you be able to gain a world class education with SIT, you will be able to do so in the world class environment of Southland.
Invercargill has excellent sporting facilities such as New Zealand's first indoor cycling velodrome, an Olympic sized swimming pool and a major indoor stadium. My council also helps to sponsor a wide range of events for recreation and entertainment.
You will also be able to enjoy our southern hospitality. Invercargill is a safe community that welcomes students from all over the world. It's also a great place if you are considering living and working in New Zealand. Southland's unemployment rate is one of the lowest in the country. As a result, we actively seek skilled migrants to come join our community.
So make the smart choice: choose SIT and Southland. I look forward to meeting you in Invercargill soon.
His Worship Mayor Tim Shadbolt
Mayor of the City of Invercargill
His Worship Tim Shadbolt is New Zealand's longest-serving Mayor. Renowned for his candour and personality, Mayor Tim won the Guinness Book of Records Award for the world's longest television interview in 2012. He clocked in at a record 26 hours – proving once and for all that politicians know how to talk!


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In Anemoi two performers carry two long tubes. There is a microphone in each tube. By changing the direction of the tubes, they catch the sound of the wind, environmental sounds or create filtering effects (the reflection of sounds against walls and buildings). The performers can also play the tubes as a percussion instrument or flute (there is one small hole in the tube through which they can blow or breathe). They also close or open the tube at one side with their hand. The performers stand on a roof or elevated location to catch the wind.
• performance: 17 December 2018 on the Experiments are More Refreshing than New Socks (Research Festival) of the Conservatory in Antwerp. The two performers were Ruben Orio and Hans Roels and stood on the roof of the Singel, the audience was watching through the windows of another building of the Singel.
In the composition Glass the audience is seated indoors, in a space with large windows, as an office or bar. In the first performance at the Oortreders festival in Belgium the audience was looking at a landscape with a street, a sports ground and trees. Through open doors they acoustically heard the outside sounds. Two performers with microphones were walking outside. Using omnidirectional, directional and close microphone techniques they brought (selections of) outside environmental sounds to the PA speakers in the audience space. Two other musicians played percussion and synthesizer, both inside and outside the audience space. Sometimes they were audible acoustically, sometimes amplified through the PA speakers, when the microphone performers picked up their sound.
Glass wants to be musical landscape art in which inside and outside spaces, performed music and indeterminate environmental sounds create an overarching, audio-visual composed space. A kind of dream space in which you are both observer and participant. The dream is collective, not individual.
• performance: 20 October 2018 by the Collectief Publiek Geluid ('Collective Public Sound') at the Oortreders festival.
Rolling Band is a work for several walking performers, moving a trolley suitcase along a trajectory with different street stones. The performers try to play together with a rhythmic click track transmitted via a wireless sender.
You can find more information on my blog (on on-site music): here.
• live audio recording (fragment) of the try-out.
Not necessarily music is a work for 'silent' musicians: people can just watch the performance or - if they want to - listen via a headphone. This work is an ode to a public, quiet place like the Krook library in Ghent (Belgium).
Thanks to technology such as smartphones, internet or headphones people can not only work, study or read at home or in their office. They can also listen to music or play piano in a public space such as a library. In this library there is a silent grand piano on which people can play or practice with headphones on. Performing music becomes a semi-private, semi-public activity in this way. Passer-bies see an intriguing visual performance but they can only guess what the musician is playing for him/herself. Just as you can only guess which messages you see people sending, or which sounds the outdoor environment - visible through large windows - is making.
This game of exposing and hiding, and creating a public space, controls Not necessarily music. In some sections the musicians are only playing for themselves. Nor the co-performers, nor the audience hears the 'original' music. In other sections they only play visually together or they listen to the same environmental sounds (arriving from a microphones placed outside the windows of the building). Finally, they also play together as 'real' musicians, listening to each other.
• performance: 23 May 2018 in the reading room of the Krook library (Ghent) by Ana Filipa Botelho (wind controller) and Quentin Meurisse (keyboard).
• live audio recording of the first performance on 23 May 2018.
• the score and extra documentation.
A living room, house or concert hall has borders, creating an inside and outside experience. Enclosed spaces - and their borders - leak and bring sounds from outside to the inside space. When the inside becomes silent - at night - the walls become audible and start to speak.
In No Room the surrounding architecture of an enclosed space is explored. Performers play outside the concert space on adjacent walls, floors, pipes, ventilation systems, etc. The sound reaches the audience through these walls and architectural objects. A microphone also records sound in real time outside the concert space and fragments of this live recording are played in the concert space.
• performance: friday 8 december 2017 in Miry Zaal (School of Arts, Ghent) by the Third Guy.
In Music Street local musicians play from houses with open windows or doors. The audience walks in a street parade together with two accompanying musicians. This results in a collage of music fragments blowing through the street. This work wants to reveal the (sound) diversity in a neighbourhood: the multiple music styles, the various ways to enjoy music and the sound transformations by the local architecture and acoustics.
• performance: saturday 21 January 2017 in the Biekorfstraat and Zeemstraat (Ghent), realised in collaboration with the neighbourhood committee de Biekorf. From 20 locations along the trajectory of the parade more than 25 (mainly amateur) musicians performed, together with Aya Suzuki (percussion) and Thomas Moore (trombone) in the parade.
• live recording of the whole performance of 21 Januari 2017.
In an open landscape musicians walk away from the audience, the performers play instruments with different loudness levels. The place and moment at which their music disappears, becomes inaudible and is absorbed by the environment is different for each performer. The audible horizon of each performer lies at a different distance from the audience. Each musician plays his own music and walks his own trajectory. This creates a spatial polyphony of distinct parts that gradually become softer and are transformed by the environment and its sounds.
• performance: 22 december 2016 in the Park Spoor Noord in Antwerp, performers: Thomas Moore (trombone), Aida Lopez (piccolo) and a bagpipe band (Metropolitan Antwerp with Adam Clarke). The music that was chosen to create this specific version of Hearizon was based on the visual and auditive experiences in this park. This music was: Eisenbahn-Lust-Walzer by J. Strauss, the song In diesen Wintertagen by A. Schoenberg and the traditional Green Hills.
• performance: 2 june 2017 at the burial site Campo Santo (Ghent), a version with trumpet (Bert Bernaerts), saxophone (Pol Mareen) and percussion (Wim Konink). The music for this specific version of Hearizon was the Renaissance Villanelle 'Io volo sopra il cielo', the folk song 'Ich habe der Fruhling gesehen' and the romantic song 'Die Jungfrau und der Tod' (Carl Loewe). This choice was based on the contradiction at Campo Santo between the beautiful (spring) nature and wide, open sky on the one hand, and the graveyard and related themes such as death and departure on the other.
• live recording: the first 10 minutes of the performance at Campo Santo (trumpet, baritone sax, glockenspiel and environmental sounds such as an air plane, train, birds, etc.).
Plain is a work for an inside space or a small, enclosed outside location. Continuous homogeneous tones or noise sounds are triggered or stopped by short sounds. All sounds are based on the frequencies, sounds, materials and architecture in the performance space. Consequently an alternation is created between static, frozen sounds and silences, after which new and old (voluntary and involuntary) sounds appear.
• performance: 27 october 2016 in the reading room of the library of de Singel (Antwerpen) at the Articulate Research Days.
• instrumentation: minimum four performers. The number of performers depends on the size and acoustics of the concert location.
• the score and extra documentation of this text score.
Beving Rozebroeken (Bebung) wants to make the concert site vibrate audibly. The main (instrument) part requires multiple performers to beat on plants and objects (trees, stones, water, park benches, garbage, bicycles, etc.) situated at the concert site or characteristic for this place. The audible, present environmental sounds are part of the performance, but the focus is more on the hidden, implicit sounds the are contained in objects and need to be brought to life. More information available on my blog.
• performance: 27 August 2016 in Rozebroeken park during the Cinepuur festival (open air film), supported by the City of Ghent.
• live recording: the first five minutes of the performance in Rozebroeken park.
• the score and the video (animated score) for the percussion part (on site-specific objects).
Open Fields is to be performed in a large (outdoor) space. Four musicians are spread at a large distance around the audience, while three other players are located near to the audience. During the performance three of the four (far-away) performers gradually move in the direction of the audience. This piece builds upon the 20th century tradition to exploit the location of instruments in a music performance. In this work I try to obtain an auditory transparency: the music should not only draw attention to itself but also to the surroundings. During a concert the audience should not only hear the music, but also experience and learn about the concert environment.
Similar to the previous composition (fl)ASH this work consists of short fragments in diverse styles that are announced or cut off by the (solo) percussion. Rasuren stands for an old correction method by which mistakes were scratched off the paper with a knife and corrections were written on top of them. Rasuren is partly inspired by the creative process of Beethoven who wrote many sketches and versions while composing.
• written for the Deleuzabelli Variations project of Paulo De Assis and the Hermes Ensemble.
• performances: 29 september 2015 in the School of Arts Ghent and 9 november 2015 in the Bijloke concert hall of Ghent.
This work was made for a visual installation of the artist Alice De Mont. The composition consists of five parts or sections that can be performed in any order, with repetitions and/or omissions. The instrumentation is free and the musicians are invited to find different ways to perform staccato sounds (with pitch) on their instrument. The timing of these short notes is written in free time, resulting in a heterophonic texture.
(fl)ASH is based upon the blinding effect of a short music fragment. If a music fragment of a few seconds is followed by a silence, a moment of dazzlement is created during which the listener can think about the fragment and try to re-imagine it. By abruptly breaking off the fragment I try to strengthen this 'internal reverb' effect (in the head of the listener).
(fl)ASH is a static composition that stresses the 'here and now'. The structure is minimalistic and suggestive: in the short term there are repetitions of (similar) fragments, but on the long term -time structures longer than 30 seconds- there are almost no references to previous fragments. Moreover, the listener can create his/her own relations between the diverse fragments.
(fl)ASH is notated as an open, graphic score for which unfinished music has to be searched. The fragments are chosen from works that were never finished by the composer, often because he/she died during the composition process or because the material production (e.g. of an opera) appeared to be impossible. The first version of (fl)ASH used fragments of unfinished compositions by J. Haydn, J.S. Bach, W.A. Mozart, Fr. Schubert, H. Berlioz, F. Mendelssohn, Pappalardo, C. Saint-Saens, Fr. Liszt, Cl. Debussy, H. Vieuxtemps, G. Mahler, A. Bruckner, L. Ornstein, B. Bartok, A. Webern and Sorabji. Fragments were also based on my own sketches and sketches of (the performers) Patrick Housen and Dennis Allegaert.
The piano and the piccolo play a central role in this work. Both go their own way: the piano in the foreground, the piccolo in the background. The other instruments of the ensemble create a environment of short, contrasting fragments around these two instruments. Some ensemble fragments -almost- develop into an independent third voice, other fragments appear just once, as a chance event.
This work tries to create a sense of musical dept or distance. The spatialisation of the performers, the timbre and the musical material serve this goal.
To synchronize the parts with their own, independent tempi, the piano functions as a kind of clock. Almost all the synchronization cues are based on this part, thus the other instruments mainly follow the piano. As in chamber music, the ensemble of 7 instruments can play together without a conductor.
This work is written for 3 pianists playing one piano. The performers play five layers or voices which have their own independent character, tempo and style. The work originated from a desire to create a work for an intimate ensemble -performers very close to each other- where each voice has enough space to develop its own personality.
The synchronization between the voices with their own tempi and character happens without a chronometer, metronome or conductor. Thanks to the physical proximity of the performers, a complex synchronization with visual and auditive cues was possible. The movements of one performer, his score and the instrument on which he is playing, are situated within the visual and aural field of the other performers.
To emphasize the timbre differences between the voices, several extended piano techniques are used, for example a piece of cloth is placed between the strings and hammers of the piano to create a very muted sound in one of the voices.
Chunks & Streams is dominated by a continuous flow of heterogeneous musical textures and events on top and after each other. Longer fragments of music are compressed into shorter fragments by presenting extreme short samples sequentially after each other or by combining different musical ideas simultaneously. The result of this manipulation of our perception of time and our perception of identity and difference is an overall form which is at the same time audible and unpredictable, a stream of sounds and musics which is chaotic but not loud nor hectic.
This composition was made in close collaboration with the Zwerm quartet. After a first rehearsal during which the performers and the composer experimented with the multiple speaker setup and with the simultaneous combination of heterogeneous musical material, the time in between the next rehearsals was used by the composer to organize and finetune the material. In the final score improvization still plays an important role but the structure and spatialization are fixed, as are the general features of the various musical textures.
Just as Threeway I (Drieweg I) this composition is a polyphonic piece in which the parts have a very high degree of independence. Very occasionally there is some active interaction between the performers. In general every performer concentrates on what he is playing and perceives the other musicians as if they are 'in the background'. This piece wasn't written for 4 specific instruments, it has an abstract score that can be played by several instruments (with certain characteristcs).
• performances: a first version of Threeway II was performed by Hans Roels and Fabian Coomans on the festival Jazz & Sounds (February 2010 - Ghent). Further performances by Manama students of the Royal Conservatory of Ghent (February 2011) and by students van York University (Music Department) in May 2011 on a concert of the seminar 'Embodiment and Experiment'.
Gort is the name of a town and river in Ireland. The region around Gort is known for its underground rivers. They disappear underground, emerge at the surface and sink underground once more in complex patterns. As a child I was fascinated by the appearance of these rivers in the middle of a field or some hundred meters before they poured in the sea. The performance techniques used in Gort produce by-sounds. Often the pitched sounds disappear in these by-sounds and a few moments later they emerge again. Whether 'undergroud' or 'overground' the music continues very intensily, very softly and full of energy. Normal bowing techniques almost aren't used in this piece.
In Soffitto a piano keyboard is connected to a computer that controls an automatic organ and xylophone. After experimenting with musical techniques, ornaments, chords and phrases that fit with these automatic instruments, Hans Roels developed algorithms (in Pure Data and Python) that change the input from the keyboard during the performance. Some details and structural elements were fixed more or less in advance, while others are totally 'open' and can be changed during the performance. Just as in live electronic music composition, improvisation and interpretation are almost inseparably connected.
• more information in the score and files (Pure data file: soffitto-1.pd, Python file: glisclus7.py), Pure Data (Pd), Python and the Python external for Pd need to be installed, this external can be found on this site.
• more information on the computer controlled music instruments, built by Godfried-Willem Raes.
Threeway (Drieweg) is a polyphonic piece in which 3 main instruments play in a seperate tempo and a fourth follows and accompanies this trio. This piece wasn't written for 4 specific instruments, it has an abstract score that can be played by several instruments (with certain characteristcs). The first version was played in the Logos Foundation on a toy piano, a melodica and two synthesizers but f.e. a performance with xylophone, clarinet, cello and accordeon or mandolin, accordeon, bass recorder and harmonium is also possible.
Threeway almost sounds as a soundscape with three clear and seperate voices that go their own way but -as if by accidence- fit together well.
Between 2007 and 2010 Hans Roels has teached live electronic music to a group of teenagers and amateur musicians. Because there aren't many compositions that can be played in these lessons he started to compose a cycle of works. These pieces are mostly based on one specific technique from electronic music. They also want to demonstrate the diversity within live electronic music. The approach, style and peformance requirements differ a lot. Often the performers need to improvise.
The software that is used in these works is the free and open source program Pure Data running on Linux, Windows and Apple. Special hardware (like certain types of synthesizers or effect machines) is avoided.
Radio South is a piece for 8, 12, 16 or 14 radios that can be performed by children or teenagers. I borrowed the idea to make a piece for radios from John Cage. Every performer has to memorize 2 places on his radio: 1 radio station (music or voice sounds) and 1 place inbetween 2 radio stations (all kinds of noises). The players are standing in the public.
A piece in which 11 computer controlled automats are being played through a MIDI keyboard. Only the key chambers of the 3 organ automats are used to produce noise. For every automat I programmed a different way of playing. Three very short parts (consisting mainly of a melody) were composed in advance. By chosing the repetitions and the order of these parts during the performance, the piece gets its shape. Slow Motion is in fact a patch in Reaktor that enables a performer to improvise with 11 music instruments. What the individual automats play, can be made in advance, generated by a (melodic) algorithm or improvised on the keyboard. Therefor, every performance sounds different.
The noise machines (like <PSCH>, <SPRINGERS>, <THUNDERWOOD>) give the performer the opportunity to play with different kinds of noise while the automatic harmonium enables the audience to hear very tiny differences in amplitude. These two characteristics are used a lot in Slow Motion.
In Point Black the pianist doesn't only play on the keys of the piano: he also plays on a cardboard box, he whistles and uses his voice. Some piano keys are prepared: rubber, bolts and other things are placed between the strings. The electronics (made with the Reaktor software) are mostly based on the granular synthesis of 3 short samples. Apart from this I also made an audio effect that modifies the dynamics of the voice and box sounds.
In Different Ways three spaces (rooms or halls) are used. Musicians move from one room to another, causing a constant change of the instrumentation in every room. Whereas in the first hall there are microphones, in the other two there are speakers. The performed music in the first hall is used as the basic material for the live electronics of the two computers. The result is played in the other two halls. In this way the processed sound becomes a part of the instrumental ensemble in those two spaces. Although the music originates from the first room, the character of the music is entirely different in the other two rooms.
This piece is a experiment with polyphony, electronics and space. The cello for example, plays together with a vibraphone in the first hall; at the same time the processed cello sound is part of a trio with recorder, violin and electronics in the second hall; simultaneously the cello is playing a quartet with euphonium, accordion, clarinet and electronics in the third hall.
In Temperate Music the music changes according to the season and the weather. I'm fond of the idea that some things are not always present but appear at one moment and then disappear again. In Temperate Music a musician plays a keyboard and seven controllers. On the screen of the computer he can see the evolution of the piece and the scales (in quarter tones) that he can use. The resulting monophonic melody is processed in the computer resulting in a more or less polyphonic piece. The sound is mainly made using FM synthesis (no samples) and partly also with physical modelling techniques.
A few hours before the performance the musician enters the characteristics about the season, wind strength and the temperature. The computation of these data results in new material that is necessary for the structure of the piece and for the realtime processing of the sound. After a first tryout of this piece (in Logos, July 2005) I realized that this basic computation took too much time in Reaktor (software). So now I have written this code in Python, here you can see this python file which generates a list of data. During the live performance some parameters are free and can be used to improvise, others can't be changed because they are part of the (weather dependent) structure of the piece. In fact, Temperate Music is a combination of an electronic instrument and a piece (or improvisation structure) that both change according to the weather.
• I have made a demonstration of the live processing: here you can hear the basic input (that is played/improvised on the keyboard). This is what the monophonic melody becomes after being processed (and with the live controllers added).
In 1998 I wrote a piece called Nowhere's Chaos which was performed several times at the November Music Festival in Belgium, Germany and The Netherlands. As the recording of the piece wasn't very successful and a strange combination of instruments was used, I found this piece rather "useless" and started using the recording as raw material for all kinds of audio electronics (experimenting with the Reaktor software). In the original version Nowhere's Chaos texts from the Zapatista uprisings in Chiapas (Mexico) were used. Colo is dedicated to the village community of Colo(tenango) in Guatemala where 2 people where killed in March 2005 during protests against a free trade agreement with the US. A few years ago I visited this village and the farmer organisation that organised the protests in March.
In 2002 I wrote the piece Ohne Worte I to commemorate the concentration camp of Breendonk (B). My enthousiasm for the applied instrumentation (2 fixed musicians -voice and viola- and two flexible musicians -of which one has to be technically minded) encouraged me to write a second part. In both parts the words of these politically inspired pieces cannot be recognised. This second part is dedicated to the Israelian technician Mordechai Vanunu who revealed the existence of Israelian nuclear bombs. As a consequece, he was captured in 1986 in Rome by the secret police of Israel and sentenced to 18 years of imprisonment. In april 2004 he left jail. During the first years in jail he wrote the poem I'm your spy. Fragments of this text are used in this piece.
In this second part of Ohne Worte the singer and viola player are now joined by a musician "playing" on a steel brush (ormally used to clean) and a fourth musician that controls the electronics. The movement of the steel brush on the surface produces sounds with an unpredictable timing (it is difficult to know exactly when a "hair" of the steel brush will "jump" and produce a sound) and dynamic curve. The electronics (made with the Reaktor software) apply both these characteristics to the voice.
This piece combines the possibilities of the player piano (controlled by a computer) and the prepared and the inside piano. While the automatic piano plays on the keys, a live performer plays pizzicati, glissandi and percussion effects on the strings, uses two ebows and changes preparations in the piano.
This polyphonic work with different simultaneous tempi and timbres develops in a non-linear way, permanently balancing between standstill and progress.
• Dubbelstuk is recorded on the CD "Machine Orchestra" in the Logos series Public Domain.
Ohne Worte is a piece with a lot of (soft) noise in which the music often disappears. The percussionist plays on a cardboard box, the singer produces a sound in between whistling and whispering and the mixer is not only used to regulate the dynamic level of the different instruments but also to generate noise. This noise of the mixer (by setting the gain at its loudest) is normaly seen as a disturbance but in this piece it is a autonomous instrument. The (almost unaudible) basis of the piece is the song Pirate Jenny of Kurt Weill.
The starting points of "How it takes place" are notions like space, place and distance. These concepts are treated literally -as physically moving in space- and figuratively -as in the spoken language where you have expressions like "a close friend" or "to be distant to someone". The latter aspect is reflected in the relationships among the musicians on the stage. Therefor "How it takes place" can also be considered as music theatre. During the performance, the musicians act as in daily life: open windows, smoke cigarettes, turn the pages of the score of another musician, etc.
Distance and space are also interpreted in a musical sense: large differences in dynamics, tempo and timbre give the listener the impression that the instruments are physically far away from each other. In short: the interaction between this physical, musical and social/emotional interpretation of distance is what the piece is all about.
The title "How it takes place" is extracted from the poem "Musée des Beaux Arts" of W.H. Auden, at its turn referring to "The Fall of Icarus" by Breughel. The spectator is drawn to the spatial effect of the composition: distant mountains, a boat sailing on the sea and a farmer working in the foreground. In the bottom right-hand corner -only a small detail- two legs of a drowning Icarus disappear in the sea. Apart from the references to death and sufferance, the painting and the poem give a good impression of the atmosphere in "How it takes place": some musicians play solo while others play together, smoke cigarettes or have already left the stage.
• There is a recording of this piece on a CD with the Belgian magazine A+ (a magazine about architecture). This recording was made by the Flemish classical radio Klara on the première of the concert where the first version of this piece was played.
• This piece was written for a concert by the Belgian ensemble Champ d'Action, on the theme of Music & Architecture. The concert was organised for a new building by the Belgian architect Stephane Beel.
Silent places -i.e. places where the level of the surrounding noise is low- are diminishing rapidly in Western Europe. These places can give the visitor rest and quiet but this peace is constantly endangered because these places are reserves in the middle of a busy and hasty society. The ambiguity of these 'Silence Reserves' is the central theme of this piece.
The audio track consists of recorded, non-modified violin and viola sounds. The violin and viola were prepared and played in different ways, one of them was the gypsy technique which consists of pulling a thin string tied to the violin string.
Run! is inspired by my image of music which is so in a hurry that it passes itself all the time, an image of music that flees away while stumbling but continuing its run. The piano plays an important role in this piece and should have a good repetition mechanism!
The tape consists of short and very fast fragments recorded on the automatic player-piano of the Logos Foundation, afterwards these fragments were edited in the Logos Studio.
This piece was written for string orchestra (6 vl I, 6 vl II, 3 vla, 2 vcl, 1cb). The title is a description of the huge sound wealth which can be found in the borderland between music and sound. Melodies, rhythms and harmonies are rather suggested than clearly pronounced. The music is very fragile, it seems as if it can fall apart any moment.
Nowhere's Chaos was written for a concert centred around 'The State' (1972) by Louis Andriessen. The latter piece by the Dutch composer is a reflection on the relation between music and politics. My inspiration wasn't the music by Andriessen but the philosophical-utopian tradition which started with the ideal state as described by Plato. The largest part of these Utopia's (like Utopia - Th. More) depicts a rich, just but at the same time authoritarian society. Only 'News from Nowhere' by William Morris is an exception because it is a part of the anarchist tradition. The text used in 'Nowhere's Chaos' is based on excerpts from this old (19th century) book which is still relevant to our times. In 'Nowhere's Chaos' fragments are also used from 'My journey with Aristotle to the anarchist utopia' by Graham Purchase, from press releases by the Zapatistas in Mexico and finally slogans used by Belgian action groups to defend the rights of refugees and illegal people are integrated in this piece.
Music as a landscape without a human logic, wherein fragments appear and disappear alternately. Nature as a ritual, slow and brutal. The still life of nature but also the anger because of the dying nature.
Phoenix was commissioned by the Walpurgis Music Theater (B). This theater asked 6 composers from Holland and Belgium to write a (short) piece of music theater on the theme of the bird which arises out of its own ashes, the Phoenix. "Phoenix" doesn't deal with this myth but with fire as an element of nature. On a text by the "first poet of Ireland" Amergin (before 700 A.D.), the singer sings and performs with imploring gestures as in ritual theatre.
In this piece I consider the player piano as an instrument different from the regular piano. The player piano is unique in its potential to produce huge polyphony (an orchestra of 88 keys), complex rhythms and superhuman speed. In "Sailing the Seas of Down Below", I exploit these possibilities to the extreme, which results in a very pianistic work: the limits of the player piano (and thus of the piano itself) are explored: thirteen-voice polyphony, combined decelerations and accelerations and fast keyboard runs that one hears as a glissando.
Sailing the Seas of Down Below consists out of two elements that seem contradictory at first: a tight melody in a steady rhythmic pattern (typically mechanical) and intertwining chromatic lines in a very free, improvisatory rhythm (typically human: with tempo changes and rubati). A machine such as the player piano is perfectly capable of solving this contradiction. In the final movement, the first few seconds of the piece are enlarged and presented as a slowly descending sound mass.
8 short songs on texts of North-American Indians. The character of the songs is very diverse: from odes to a seal to slanging matches and exorcist rituals.


text:
Bläsi oder Blaesi (schweizerdeutsche Variante von Blasius) ist der Familienname folgender Personen:

 August Blaesi (1903–1979), Schweizer Bildhauer
 Christoph Bläsi (* 1960), deutscher Buchwissenschaftler
 Franz Bläsi (1893–1963), deutscher Pädagoge und Politiker (CDU)
 Roland Blaesi (* 1932), Schweizer Skirennläufer

Siehe auch:
 Blasi
 Blesi

redpajama_set_name: RedPajamaWikipedia


The supramolecular complex formed between protein and designed molecule has become one of the most efficient ways to modify protein functions. As one of the more well-studied model systems, 14-3-3 family proteins play an important role in regulating intracellular signaling pathways via protein-protein interactions. In this work, we selected 14-3-3σ as the target protein. Molecular dynamics simulations and binding free energy calculations were applied to identify the possible binding sites and understand its recognition ability of the supramolecular inhibitor, the tweezer molecule (CLR01). On the basis of our simulation, major interactions between lysine residues and CLR01 come from the van der Waals interactions between the long alkyl chain of lysine and the cavity formed by the norbornadiene and benzene rings of the inhibitor. Apart from K214, which was found to be crystallized with this inhibitor, other lysine sites have also shown their abilities to form inclusion complexes with the inhibitor. Such non-specific recognition features of CLR01 against 14-3-3σ can be used in the modification of protein functions via supramolecular chemistry.
Recently, the intriguing strategies using supramolecular chemistry in the modification of protein functions via host-guest interactions have attracted extensive interests. Some prototypical applications include inhibition of proteases (Peczuh and Hamilton, 2000; D'Acquarica et al., 2011), enhancement of solution (Perret and Coleman, 2011), and manipulation of enzyme activities (Pan et al., 2018). To achieve this, surface exposed charged residues like lysine and arginine are usually used as the target recognition sites, which can form the supramolecular complexes with macrocycles, e.g., cycloaramide (Pan et al., 2018), p-sulfonatocalixarene (Thomas and Ward, 2005; Perret et al., 2006), crown ethers (Shimojo et al., 2006) and cyclodextrins (Kano and Ishida, 2007). As one of typical systems, 14-3-3 proteins (Aitken, 2006) have been considered to be the perfect target used for regulation of protein-protein interactions (PPIs) via supramolecular inhibitors.
14-3-3 proteins are a unique class of regulatory, phosphoserine/threonine-binding proteins found in nearly all eukaryotic cells (Hermeking, 2006). There are seven human 14-3-3 family members (α/β, ε, η, γ, τ/θ, σ, and ζ) according to amino acid sequences (Yang et al., 2006), while plants contain up to 13 isoforms and 2 isoforms in yeast (Fu et al., 2000; Powell et al., 2003). More than one thousand binding partner proteins of the 14-3-3 domain have been identified including transcription factors, signaling molecules, tumor suppressors, biosynthetic enzymes, cell cycle regulation, cell proliferation, protein trafficking, metabolic regulation, and apoptosis (Fu et al., 2000; Aitken, 2006; Hermeking, 2006). Although they show no enzymatic activity by themselves, 14-3-3 proteins can alter the conformation, localization, stability, phosphorylation state as well as activity of a target protein via PPIs (Muslin and Xing, 2000; Tzivion et al., 2001; Aitken, 2006; Aghazadeh and Papadopoulos, 2016). Recently, 14-3-3 proteins have also been recognized to have chaperone-like functions (Sluchanko and Gusev, 2017). Binding of the 14-3-3 domain to its target proteins often occurs in a phospho-specific manner where it binds to one of two consensus sequences of their target proteins, RSXpSXP, and RXXXpSXP (Yaffe et al., 1997). On the other hand, 14-3-3 also interacts with proteins in a phosphorylation independent manner, e.g., the interaction with a specific peptide motif of the bacterial toxin exoenzyme S (ExoS) from Pseudomonas aeruginosa (Ottmann et al., 2007b). Their interaction is often considered to be one of the most ideal models for understanding PPIs.
The understanding of PPIs in the development of peptide-like inhibitors has been of particular pharmaceutical interest (Aeluri et al., 2014). Indeed, several attempts have been made to develop small-molecule inhibitors against the PPIs involved 14-3-3 proteins (Corradi et al., 2010; Bier et al., 2013; Thiel et al., 2013). Herein, we will discuss one of well-studied inhibitors called tweezer (CLR01) and how it interacts with 14-3-3σ.
The function of this inhibitor is versatile, e.g., regulating the aggregation of α-synuclein (Acharya et al., 2014), modulating the aggregation propensity and cytotoxicity of huntingtin protein (Vöpel et al., 2017), and inhibiting the activity of PARP-1(Wilch et al., 2017). The tweezer molecule is a water-soluble belt-like molecule with a torus-shaped cavity surrounded by alternating aromatic and aliphatic rings, which has the specificity of recognizing either lysine or arginine. The anionic phosphate groups on tweezer can draw the cationic side chains of lysine or arginine into its cavity to form a tight ion pair but with different binding affinity (Klärner and Schrader, 2013). The tweezer binds arginine with much weaker affinity than lysine (Fokkens et al., 2005; Dutt et al., 2013). The crystallographic structures of the 14-3-3σ/tweezer complexes were resolved by Bier et al. (2013) which shows that the alkyl chain of K214 is fully surrounded by the tweezer molecule. This can provide an ideal initial model to understand the protein-inhibitor interactions at the atomic level. Interestingly, 14-3-3σ contains 17 surface exposed lysine residues, which could also have possible stable interactions with tweezer. Indeed, the QM/MM binding energy calculation did show some other lysine residues, e.g., K27, K77, K141 and K195, can be recognized by the tweezer molecule. Meanwhile, the isothermal titration calorimetry (ITC) data also shows at least two independent binding events with different affinities when tweezer and 14-3-3σ occur together in solution (Bier et al., 2013). Obviously, only experimental ways cannot provide a full understanding of the inhibitor binding mechanism. Theoretical simulation represents one of useful ways to tackle molecular interactions from a micro-perspective. Such research has been reported in many peer-reviewed literatures on various biomolecule systems (Cao et al., 2012; Gao et al., 2015; Zhang and Zheng, 2018; Zheng and Lazo, 2018).
Herein, combining the MD simulation and binding free energy calculations, we try to locate the possible binding sites of 14-3-3σ by the tweezer molecule. This might provide a chance to understand the inhibition mechanism of protein-protein interactions from a micro-perspective, esp. for the 14-3-3σ protein. This could be helpful in the future development of 14-3-3σ inhibitors with better potency.
There are many X-ray structures that have been solved for 14-3-3σ protein (Benzinger et al., 2005; Wilker et al., 2005; Molzan et al., 2010, 2013; Schumacher et al., 2010a,b; Roglin et al., 2012; Rose et al., 2012; Anders et al., 2013; Bier et al., 2013; De Vries-van Leeuwen et al., 2013; Thiel et al., 2013; Joo et al., 2015; Milroy et al., 2015; Doveston et al., 2017; Sijhesma et al., 2017; Sluchanko et al., 2017a,b; Stevers et al., 2017; Prokop et al., 2018). For example, Bier et al. (2013) reported the complex of tweezer/K214 (PDB entry code 5OEH) with a resolution of 2.35 Å. This structure will be employed in this work to simulate the interaction between the inhibitor and K214. As we have mentioned above, there are 17 surface exposed lysine residues shown in Figure 1. To fully understand the binding affinity of 14-3-3σ protein with this inhibitor, we have to analyse all possible lysine binding sites. Moreover, recent QM and QM/MM studies have shown that tweezer can form complexes with arginine or lysine residues, but that studies also displayed that the binding affinity of arginine is much weaker than lysine (Dutt et al., 2013). Therefore, only recognition status of lysine residues will be considered in this work.
Figure 1. Topological depictions for 14-3-3σ monomer and tweezer molecule. (A) Structure of tweezer molecule. (B) Definitions for helices of 14-3-3σ. Cartoon style used for 14-3-3σ. The helix is defined as α1, α2, α3, α4, α5, α6, α7, α8, and α9 from N-terminal to C-terminal of 14-3-3σ (PDB entry code 5OEH).
In order to completely understand the interactions between all lysine residues and the inhibitor of tweezer molecule, we should consider all possible binding models. Here, an apo structure for 14-3-3σ was adopted as the initial structure [PDB code 1YZ5 (Benzinger et al., 2005) at a resolution of 2.8 Å] except K214 in the subsequent docking simulation.
The docking method was used to construct the initial complex structures. The partial charges for both receptor (14-3-3σ) and ligand (tweezer) were assigned using AutoDockTools (Sanner, 1999) with Gasteiger method (Gasteiger and Marsili, 1980). A grid map of 60 × 60 × 60 points with 0.375 Å grid spacing was generated using AutoGrid module based at the center of the α carbon atom of each lysine residues (Morris et al., 2009). The Lamarckian genetic algorithm (Morris et al., 1998) was applied as the searching approach. For each lysine sites, a total of 1,000 conformations from docking simulation were clustered according to the RMSD criterion within 2.0 Å. We carefully checked all conformations to see if the side chain of lysine can be inserted in the cavity of tweezer. The conformer with the lowest binding energy will be selected out as the initial structure for further MD simulation and binding free energy calculation. In our docking simulations, the side chain of lysine residue and tweezer were set to be flexible, whereas other protein parts remained in their crystal positions. The docking results for every lysine site can be found in the Supporting Information.
All resulted complexes were fully solvated in a rectangular box of TIP3P (Jorgensen et al., 1983) water with sodium ions added to neutralize the whole system. One typical system consists of more than 48,500 atoms with the box size about 87 Å × 74 Å × 93 Å. The periodic boundary conditions and a cut-off of 12 Å for nonbond interactions were applied. To correctly describe the long-range electrostatic interactions, the particle mesh Ewald (PME) algorithm (Darden et al., 1993) was employed. The positions of water molecules were relaxed by 9,000 steps of steepest descent and 1,000 steps of conjugate gradient minimization approach with all of the protein and ligand molecules fixed at their original positions. A further 10,000 steps of conjugate gradient full minimization were carried out for the total system. The optimized systems were gradually heated to 300 K in 200 ps in the NVT ensemble, followed by 200 ps equilibration in the NPT ensemble at 1 atm and 300 K. Subsequently, a further 300 ns MD simulations were performed for data analysis. Newton's equations of atomic motion were integrated by the Verlet algorithm with 2 fs time step. SHAKE algorithm (Ryckaert et al., 1977) was applied to constrain those covalent bonds involving hydrogen atoms. To correctly describe the tweezer molecule in our MD simulation, the standard Amber general amber force field (GAFF) (Wang et al., 2004) generation procedure was used to generate force field parameters for tweezer. First of all, the geometry of tweezer molecule was optimized at HF/6-31G level of theory using Gaussian09 suite of program (Frisch et al., 2009). The restrained electrostatic potential (RESP) protocol (Bayly et al., 1993) was employed to obtain the partial atomic charges at the B3LYP/6-31G* level of theory after geometry optimization. The force field parameters for the ligands can be generated using the Antechamber program. All MD calculations were performed using the AMBER12 suite of programs (Case et al., 2012) together with AMBER ff14SB force field (Maier et al., 2015) for 14-3-3σ.
To quantitatively assess the binding affinity of tweezer with different lysine sites of 14-3-3σ, it would be useful to calculate the corresponding binding free energies. In this work, molecular mechanics Poisson Boltzmann (or generalized Born) surface area (MM-PB/GBSA) (Srinivasan et al., 1998; Lee et al., 2004) were employed to calculate the binding free energies.
ΔGcomplex, ΔG14−3−3σ and ΔGtweezer are denoted as free energies of the complex (tweezer/K), the protein (14-3-3σ) and the ligand (tweezer), respectively. For MM-GBSA approach, only one MD trajectory is needed to get these values via a statistical average way. The solvation free energy (Gsol) can be principally divided into both polar (GGB) and non-polar (Gnp) terms. The non-polar solvation free energy comes from the surface formation and van der Waals interactions between the solute and solvent, which can be evaluated by the equation of γSA + b, where γ = 0.0072 kcal·Å−2 and b = 0.0 kcal·mol−1. The SA denotes the solvent's accessible surface area, which was estimated using the program MSMS (Sanner et al., 1996). The polar solvation part is calculated by solving the Generalized Born equation (Onufriev et al., 2000). Here, dielectric constants for the solute and solvent were set as 1 and 80, respectively. For each complex system, binding energies were averaged over 2,000 frames of the last 200 ns MD trajectory. Entropy can be estimated from changes in the degrees of freedom including translation, rotation, and vibration. These entropy terms are functions of the mass and moments of the inertia of molecule, thus can be easily calculated using the standard equations of statistical mechanics. Specifically, contributions to the vibrational entropy were calculated using the normal mode analysis approach (Case, 1994). The −TS was averaged over 200 snapshots of the MD trajectory.
As we have mentioned above, there are total of 17 lysine residues located on the surface of 14-3-3σ. A thorough investigation of recognition ability of the tweezer against all these lysine sites could provide a complete understanding of the interactions between the tweezer molecule and the protein. To get an accurate binding affinity comparison, a 1:1 inclusion ratio was employed in this work. Moreover, except tweezer/K214 complex model, all other initial complex models were prepared by a docking approach using AutoDock tool. All initial models (Figures S1-S11 and S13-S16) after AutoDock can be found in supplementary file. Subsequent 300 ns separate MD simulations were carried out to get fully relaxed complex structures.
According to the dimeric characteristics of the 14-3-3σ protein, we simply classify these lysine residues into four classes for convenience. The first class (I-type) contains the lysine residues existing at the 14-3-3 dimer interfacial region, which includes five lysine residues like K9, K11, K27, K32, and K87. The second class (II-type) consists of lysine residues (K49 and K122) located inside the 14-3-3σ active cavity. The third class of lysine residues (III-type) is located at the edge of binding groove. Five lysine residues, K68, K77, K140, K141 and K214, belong to this class. The fourth type of lysine residues (IV-type) locates on the reverse side of the 14-3-3σ protein active groove, which includes K109, K124, K159, K160, and K195. To illuminate our classification, a schematic plot to show all lysine residues was given in Figure 2.
Figure 2. Cartoon representation for the classification of all surface exposed lysine residues of 14-3-3σ. Two chains are colored in red and cyan, respectively. (A) I-type, (B) II-type, (C) III-type, and (D) IV-type.
The crystal structure of 14-3-3σ complexed with tweezer has been reported. Therefore, it would be better to compare both docking model and the X-ray structure first. As shown in Figure 3, we can find out that except the orientation, the tweezer molecule in two models locates nearly at the same position, and can recognize the lysine residue very well. One of the phosphonate groups is coordinated by the lysine residues as expected. Due to its belt-like or torus-shaped topology of tweezer molecule, possible rotation around the side chain of K214 could happen when it binds lysine residues. Therefore, we believe all docked models obtained using AutoDock 4.2 (Morris et al., 2009) can be applied in our dynamic simulation to tackle the recognition mechanism. Of course, for the tweezer/K214 complex model, the X-ray structure [PDB entry code 5OEH (Bier et al., 2013)] will still be employed as the initial model.
Figure 3. The superimposed structures of the X-ray structure and the docked structure for tweezer included K214. The tweezer molecule and K214 are plotted using stick style, in which carbon atom is colored in yellow for X-ray tweezer, while blue for the structure after docking. (A) Top view of the superimposed structures, (B) side view of the structures.
Throughout the 300 ns MD simulation, the overall 14-3-3σ protein maintains its topology very well, judged by the backbone atom root mean square deviation (RMSD) of 2.30 ± 0.44 Å plotted in Figure 4A. One snapshot extracted from the MD trajectory was depicted in Figures 5A,B. As shown in Figure 5A, K214 is situated at α9, which stays at the edge of the protein binding groove. Once the tweezer/K214 inclusion complex is formed, there is no big fluctuation for the overall conformation of the protein during the dynamics. The side chain group of K214 can stay inside the cavity of tweezer molecule very stably via various interactions. First of all, a stable ion pair is formed between one of negatively charged phosphate groups (P1) of tweezer and the positively charged amino group of lysine residue, judged by the distance of dP−N = 4.02 ± 0.28 Å in Figure 4B. Although occasionally flexibility of this phosphate group can be observed during the simulation, further dynamics running can recover their interaction. Except the positively charged amino group of lysine residue, its long alkyl chain forms quite stable hydrophobic interactions with both norbornadiene and benzene rings. In fact, the topological structure of tweezer requires the recognized residue to have a long side chain. Clearly, lysine and arginine are two residues that match the requirement. Interestingly, some other supramolecules like calixarene (Perret et al., 2006) or cyclo-aramide (Pan et al., 2018) shows their recognition specificity with lysine or arginine in cytochrome c.
Figure 4. (A) Backbone RMSD as a function of simulation time for the tweezer/K214 complex system with the X-ray structure as the reference. (B) Distance between the nitrogen atom of amine group of K214 and the phosphorus atom of the phosphate group of the tweezer molecule throughout the MD simulation.
Figure 5. (A) Snapshot of tweezer/K214 complex extracted from the MD trajectory of the centroid conformation of the maximum cluster of the last 200 ns. (B) Zoom-in view representation. (C) 2-D Protein-ligand interaction depictions of K214/tweezer complex by the end of MD simulation (300 ns). Green circles represent hydrophobic residues, purple circles represent polar residues, red ring represent acidic residues, and blue interior rings represent basic residues. Hydrogen bonding interactions are drawn with an arrowhead, sidechain in green and backbone in blue. Green benzol rings with a "+" describe an arene–cation binding; two benzol rings, an arene–arene binding. The solvent accessible surface area is plotted onto the atoms in blue smudge for ligand and over the constituent atoms as turquoise halo for receptor residues, respectively. (For detailed interpretation of the color definitions, the reader is referred to the web version of this article (Clark and Labute, 2007).
On the other hand, a relatively weak hydrogen bond network formed between the second phosphate group (P2) and 14-3-3σ can be observed, judged by the hydrogen bond occupancy analysis, e.g., only 22% of dynamic time between the hydroxy of second phosphate group and the carboxylate of D215. In fact, this phosphate group is exposed to water during most of the dynamic time. Furthermore, to shed more light onto the interaction patterns between the tweezer molecule and surrounding residues, a diagrammatic plot was given in Figure 5C. Besides the salt bridge formed between K214 and the phosphate group (P1) of tweezer molecule, major interactions should be attributed to the long alkyl chain of K214 with the benzene and norbornadiene units of tweezer. Moreover, the tweezer/K214 complex seems to be surrounded by other residues like E210, Y213, D215, T217 and L218, although no direct interactions like hydrogen bond can be observed.
Of course, MD simulation can only provide qualitative descriptions of the substrate binding information. Further quantitative assessment of the recognition ability of 14-3-3σ by tweezer is highly necessary. Here, the binding free energy was obtained by MM-GBSA method. As listed in Table 1, ΔGbind calc= −2.54 kcal·mol−1 was obtained for tweezer/K214 complex, which has as large as ~4–6 kcal·mol−1 difference from experimental data. Such big difference from experimental observation might suggest that K214 is not the preferred binding site by tweezer molecule in solution phase. In fact, such an observation has also been realized by Bier et al. (2013). These authors carried out classical MD simulations for the tweezer/K complexes, and then calculated their total energies via B3LYP-D2/CHARMM method, which were then used to rank the binding possibility for different lysine sites. They further proposed some other lysine binding sites even better than K214 could also be reached by the tweezer molecule. Our results based on MM-GBSA binding free energy calculation can reproduce their conclusion that there is not only one lysine site for tweezer. In other words, more comprehensive dynamics simulations and corresponding binding affinity investigations should be carried out for other lysines of 14-3-3σ protein.
Table 1. Binding free energy for tweezer/K214 complex and decomposition to electrostatic interaction, van der Walls interaction, solvation free energies, and entropy.
Nevertheless, we still have some useful information based on MD results for tweezer/K214 complex. Basically, the binding free energy is generally decomposed to polar (ΔEele + ΔEGB) and non-polar (ΔEvdW + ΔEsurf) contributions. According to Table 1, total polar contribution is calculated to be 13.16 kcal·mol−1, while −37.59 kcal·mol−1 for non-polar contribution. Although an ion-pair is formed between K214 and tweezer, the overall electrostatic interaction between protein and tweezer shows a large positive number. This cannot be mediated by solvent effect. Therefore, we might simply consider that the ion pair can only function upon positioning the tweezer molecule. Such an observation also agrees with our hydrogen occupancy analysis. On the other hand, the van der Waals interaction has a significant stabilization effect during the inclusion complex formation. At the same time, considering the absolute values of ΔH and TΔS, the inclusion of 14-3-3σ by tweezer is an enthalpy driven pathway.
We have mentioned above that some residues can be found to be very important during the binding of tweezer according to 2-D Protein-ligand interaction depictions shown in Figure 5C. To get a more quantitative understanding of contributions from all these residues, we further conducted the binding free energy decomposition calculations per residue. Corresponding results can be found in Table S1. As large as −8.98 kcal/mol can be found for the contribution from K214, which means K214 constitutes the major binding free energy. However, D214 shows 2.31 kcal/mol to the binding, which is completely negative to whole substrate binding. Other residues like E210, T217, and L218 show some moderate contributions to binding affinity. Obviously, the relatively low binding affinity found for K214 by tweezer based on our simulation could be a combination effects from all residues.
It is well known that the active 14-3-3 protein should be in its dimer structure (Jones et al., 1995; Messaritou et al., 2010; Woodcock et al., 2015). However, previous study has shown that the inhibitors can be bound around the dimer interfacial region and thus disrupt the function of 14-3-3 proteins (Ehlers et al., 2018). Therefore, it would be useful to carry out MD simulation to understand the binding characteristics for those lysine residues at the interface between two monomers. Here, we only employ the monomer structure in our simulation, which could be used to evaluate the binding affinity compared to other lysine sites. The I-type includes the lysine residues such as K9, K11, K27, K32, and K87, which distribute on several helices (α1~α4). As shown in Figure 6, K9 and K11 locate at the middle of α1, and are also deeply embedded into two helices of two protein chains. On the other hand, the side chain of K87 points toward the cavity formed between two monomer chains. We can simply postulate that these three lysine residues could not be easily reached by the tweezer molecule on the basis of its size. To this point, we then focus on the K27 and K32 for the possible I-type lysine binding sites. Corresponding snapshots extracted from MD trajectories are plotted in Figure S17.
Figure 6. The zoom-in view for I-type lysine residues on the dimer interface of 14-3-3σ dimer. (A) K9, (B) K11 and (C) K87.
According to the original crystal structure, the side chain of K27 seems impossible to be recognized by tweezer molecule. However, due to flexible docking strategy, we can construct a stable initial model of tweezer/K27 inclusion complex. Indeed, thanks to the strong interaction between alkyl chain of lysine and norbornadiene/benzene units of tweezer, the side chain of K27 stays inside the cavity of tweezer molecule quite stably throughout the MD simulation. On the other hand, a stable ion pair can still be formed between the phosphate group and the amino group of K27, evidenced by the distance of dP−N = 4.05 ± 0.15 Å in Table 2. Besides this, the hydrogen bond formed between one of the two phosphate groups of the tweezer molecule and imidazole group of H106 can be observed during the simulation. A total of 42.87% hydrogen occupancy rate was found for the interaction between H106 and tweezer. To get a quantitative assessment for the binding affinity, we have also calculated the binding free energy using MM-GBSA method. As listed in Table 2, the binding free energy is calculated to be ΔGbindcalc = −12.78 kcal·mol−1 for K27 recognized by tweezer, which means much stronger binding than K214. Similar to the recognition at the site of K214, the non-polar terms play the major contribution. According to Table S2, the polar (ΔEele + ΔEGB) and non-polar (ΔEvdW + ΔEsurf) contributions were calculated to 7.47 kcal·mol−1 and −43.53 kcal·mol−1, respectively.
Table 2. Binding free energies for tweezer/K complexes and the ion pair distance.
On the other hand, the K32 is located at the terminal region of α2. Its side chain could show relatively large flexibility, which makes the K32 easily recognized by tweezer during MD simulation. As we can see from Figure S17, the alkyl side chain of K32 is stably inserted into the cavity of tweezer molecule. At the same time, the stable ion pair is maintained between the negatively charged phosphate group and the positively charged amino group with dP−N = 3.97 ± 0.20 Å. A large binding free energy for tweezer/K32 (ΔGbindcalc = −9.29 kcal·mol−1) also indicates that K32 cannot be ignored for the inhibitor design.
Although K27 and K32 are located at the interface between two monomer chains, their positions still allow them to be recognized by tweezer. Moreover, the binding free energy for these two lysine residues indicates much stronger binding affinity than the tweezer/K214 complex. On the basis of our simulation, those residues located around the interfacial region of two proteins cannot be simply ignored. Such kinds of observations are not unique in 14-3-3 proteins. Protein engineering trials have been proposed for residues located at the dimer interface for 14-3-3 proteins, since the dimeric structure was proposed to be essential for the activity and functions of 14-3-3 proteins (Messaritou et al., 2010). For example, a previous site directed mutagenesis study showed that the dimeric status of 14-3-3ζ proteins is regulated by the phosphorylation of S58, which is situated within the dimer interface (Woodcock et al., 2003). Recently, the ligand that targets the dimerization interface of the 14-3-3 adapter protein has been reported by Ehlers et al. (2018). Moreover, the disruption of dimeric 14-3-3 structure by the sphingosine-like molecules and N-alkylated trimethyl ammonium molecules has been proposed to be a novel method to the anti-cancer therapeutics (Woodcock et al., 2015).
Two lysine residues including K49 and K122 belong to II-type. The K49 plays an important role in the binding between 14-3-3 proteins and the binding partner proteins from the analyses of nine crystal structures (Thiel et al., 2013). At the same time, if the active site of 14-3-3σ, which includes the K49 and K122, is occupied and competitively blocked by the small molecules, the activity of the partners will be changed accordingly (Würtele et al., 2003; Zhao et al., 2011).
As displayed in Figure 2B, K49, and K122 stay deeply inside the active site of the 14-3-3σ protein, which shows a deep internal amphipathic groove formed by several helices like α3, α5, α7, and α9. In particular, K122 locates on α5, which forms the bottom of the binding groove of 14-3-3σ protein together with α7. On the other hand, the helices of α3 and α9 constitute two side faces of the binding groove, which result that there is not enough space to accommodate the tweezer molecule in Figure S9. Therefore, the recognition of K122 by the tweezer molecule should not be expected, and no further simulation will be conducted here. K49, on the other hand, is found to be in the middle of α3, which can be encapsulated by the tweezer cavity after the initial AutoDock simulation in Figure S3. However, this inclusion complex shows instability during the MD simulation. According to the geometry evolution along the MD time, we can find that side chain of K49 does not stay inside the tweezer cavity anymore. To illustrate this, we then plotted five snapshots along the dynamics time course in Figure S4. Clearly, the tweezer molecule cannot form a stable inclusion complex with either the K49 or K122. Therefore, we might simply discard further discussion of II-type lysine binding sites.
Fundamentally, the binding groove of 14-3-3σ is a canyon-like shape. All lysine residues belonging to III-type, K68, K77, K140, K141 and K214, can be found at the edge of the groove from Figure 2C. Since the tweezer/K214 complex has been discussed to some extent above, we will focus on the rest of the lysines in this section. Their snapshots obtained from MD trajectories are illustrated in Figure S18.
K68 locates in the loop region between α3 and α4. Throughout the MD simulation, the side chain of K68 can be included by the cavity of tweezer, but shows relatively large flexibility. Indeed, much larger fluctuation and longer average distance can be found for the ion pair (dP−N = 4.58 ± 0.99 Å), which resulted in a weak recognition (ΔGbindcalc = −4.84 kcal·mol−1) in Table 2. Nevertheless, as shown by the 2-D protein-ligand interaction diagram in Figure S6, a similar interaction pattern between K68 and tweezer can be still observed compared to tweezer/K214 complex.
We can also locate the same interaction patterns in other type-III lysine sites, although different recognition ability can be found. For example, the K77, which belongs to the type-III lysines, is located at the same loop region as K68. During the MD simulation, the side chain of K77 is deeply embedded into the cavity of tweezer molecule, but forms a very strong ion pair via its amine group and the phosphate group with dP−N = 4.22 ± 0.77 Å. On the other hand, it shows much stronger recognition ability than K68. The calculated binding free energy for tweezer/K77 complex is about −12.84 kcal·mol−1. The ion pair distance for the tweezer/K68 complex is about 0.36 Å longer than that in the tweezer/K77 system. A common residue of E76 seems to cause the difference. From Tables S7, S9, we can see that the E76 contributes negatively to the stability of the tweezer/K68 system, while positively to the tweezer/K77. Structurally, the E76 shows no direct contact with two lysines or the tweezer molecule. Therefore, the different contributions of E76 to the binding free energies might come from its interactions with other protein residues.
The other two type-III lysine residues, which are located at the edge region of active groove, are K140 and K141. However, according to our MD simulation, the side chain of K140 cannot be well enclosed by the tweezer cavity in Figure S12. On the contrary, K141 can form a quite stable complex with tweezer judged by ΔGbindcalc = −12.80 kcal·mol−1. Again, the interaction patterns between K141 and the tweezer are much like the binding of tweezer/K214.
Those lysine residues located the edge of the amphipathic groove of 14-3-3σ can form inclusion complexes with the tweezer so that the space of groove will be changed to affect the activity of the chaperone protein 14-3-3σ. Thus, the partner proteins are inactivated either by cofactor capture or by complexation with lysine residues, most likely in the vicinity of the active site, which shows for the III-type lysine residues (Wilch et al., 2017). According to the crystal structure of 14-3-3/ExoS (Ottmann et al., 2007b; Karlberg et al., 2018) and tweezer/K214 (Bier et al., 2013), we can find that the C-terminal of the ExoS is occupied at the same position for tweezer, which further indicates that the 14-3-3/ExoS PPI system could be disrupted by the tweezer molecule and result in the loss of activity of ExoS.
In addition to the above lysine residues, other lysine residues are located at the reverse side of the active groove of 14-3-3σ. Further, those lysine residues are also far away from the dimer interface of 14-3-3σ. Therefore, their recognition status cannot have direct impact to the PPIs involved 14-3-3σ. However, if these lysine residues can be recognized by tweezer, substantial conformational change might be expected.
First of all, the K124 is found to occur in the α5, which cannot be well recognized by the inhibitor due to obvious steric hindrance as shown in Figure S10. For other IV-type lysine residues like K109, K159, K160 and K195, quite stable inclusion complexes formed with tweezer can be obtained via our long time MD simulations. Figure S19 plots all snapshots for the IV-type lysines complexed with tweezer molecule. Not surprisingly, the interaction patterns with tweezer are generally the same. For example, stable ion pairs are formed between one of phosphate groups of tweezer molecule and the –NH3+ group of lysine, evidenced by dP−N = 4.00 ± 0.18 Å for K109, 4.28 ± 0.73 Å for K159, 3.94 ± 0.20 Å for K160 and 4.03 ± 0.17 Å for K195. The long alkyl chain of lysine can be well accommodated by the cavity formed by benzene/norbornadiene rings. Binding free energy calculations also confirm that these residues can be bound within the cavity of the tweezer molecule, albeit the binding affinities have some differences, e.g., −6.62 kcal·mol−1 for K109, −9.26 kcal·mol−1 for K159, −3.84 kcal·mol−1 for K160 and −14.31 kcal·mol−1 for K195. Notably, IV-type are not close to the conventional 14-3-3 protein binding groove. Such pretty strong binding affinities might indicate that the recognition of the lysine residues by the tweezer might not have specificity, if we take all above binding free energy calculations together.
As we have presented above, the recognition patterns of surface exposed lysine residues of 14-3-3σ by the tweezer (CLR01) molecule were explored using MD simulation approach. Our results clearly suggest that pretty stable supramolecular complexes can be formed between 14-3-3σ and the inhibitor. First of all, due to hydrophobic characteristics of the inner concave cavity formed by benzene and norbornadiene rings of the ligand, the long alkyl side chain of lysine seems to be the major factor to provide the binding affinity. Apart from this, additional stabilization comes from the stable ion pair formed between the phosphate group of CLR01 molecule and the amine group of lysine residue. In particular, the MD simulations and binding free energy calculations also indicate that this small molecule can recognize 10 of 17 lysine residues very well, which means no preferential lysine recognition site, although the reported X-ray structure shows co-crystallization of only K214 with the inhibitor. This is not unexpected, since previous QM and QM/MM MD simulations have also suggested that there has to be the second lysine-binding site for this tweezer molecule. At the same time, the isothermal titration calorimetry (ITC) measurements clearly revealed a two-phase course, which means at least two independent binding events with different affinity (Bier et al., 2013). This phenomenon is not unique. A recent study for the interactions between CLR01 and poly[ADP-ribose]polymerase (PARP-1) also show distinct multiple lysine recognition site (Wilch et al., 2017). More interestingly, such a recognition ability of CLR01 was considered to be an efficient inhibition method. Thanks to the cavity topology, there are other supramolecules that cannot specifically recognize the lysine residues, e.g., the para-sulfonato-calix[n] arenes (Perret et al., 2006). Indeed, in our binding free energy calculation, ΔGbindcalc = −2.54 kcal·mol−1 for tweezer/K214 complex, which demonstrates a large difference from the experimental measurement of −6~-8 kcal·mol−1. Therefore, other lysine residues cannot be simply ignored if we want to investigate the interaction between tweezer and 14-3-3σ protein.
Another interesting issue is that the 14-3-3σ protein was shown to be active upon the dimerization, which exhibits a U-shape topology and the N-terminal helices constitute the dimer interface. This U-shape groove formed by either homo or hetero dimerization seems to be a conserved phenomenon in 14-3-3s (Jones et al., 1995; Messaritou et al., 2010). On the other hand, each monomer has its own canyon-like ligand binding groove. Such kind of structural characteristics have been suggested to be essential for 14-3-3s stability and functional activity, e.g., 14-3-3ζ (Messaritou et al., 2010). When 14-3-3s function as adaptor proteins in the functionally regulation of other proteins, the U-shaped groove serves as the key point via interaction with two motifs on single or multiple client proteins (Alblova et al., 2017; Chalupska et al., 2017; Karlberg et al., 2018). Inhibitors can thus be designed based on the following strategies, e.g., blocking client proteins moving in the binding groove or breaking the dimerization. If we carefully check the positions of surface lysine residues, we can see that the non-specific binding affinity seems to be quite suitable for supermolecular inhibitor design. As shown in Figure 1, the surface exposed K214 is situated at the beginning of the last C-terminal helix (α9), which is ready for forming an inclusion complex with the tweezer molecule. In fact, once the formation of the tweezer/K214 complex is completed, the binding channel of the external client protein will be clearly blocked (Bier et al., 2013). Meanwhile, the tweezer molecule also shows pretty strong interactions with some interfacial lysine residues on the basis of our MD simulation and binding free energy calculations. Such interactions can affect the dimerization without question. In other words, the non-specific recognition ability of the tweezer molecule against surface lysine residues could facilitate its inhibition to 14-3-3 proteins.
Nevertheless, detailed analyses of the ligand binding canyon of the monomer protein chain still stay at the core position. As we have mentioned above, including K214, there are 9 other lysine residues, which are ready for inclusion by the tweezer cavity. MD simulation can only provide some general idea of how the inhibitor bound to the lysine residues. It cannot give quantitative evaluation of contributions from surrounding residues. Based on our MM-GBSA calculations, further decomposition per residue calculations were carried out for all stable complexes. All results are summarized in Tables S1–S19. More importantly, if we carefully analyze all data presented there, we could find that the van der Waals interactions between lysine and tweezer dominate the binding energy. To illuminate this, we then plotted the comparison between calculated EvdW and Etotal in Figure 7. Obviously, if we do not consider other residues close to the lysine residue, the contributions to the binding free energy from lysine residues are generally very close.
Figure 7. Comparison of EvdW and Etotal for K27, K32, K68, K77, K109, K141, K160, K195, and K214.
Of course, our model used in this work only considered one monomer chain of 14-3-3σ protein. To get a more complete understanding of the inhibition mechanism, we might include the whole protein in the simulation in the future. On the other hand, since no external protein is included in our simulation, we cannot evaluate the detailed effects of the tweezer molecule in the regulation of protein-protein interactions. The simulation presented here can still shed some insights into the development of new inhibitors. For example, although the tweezer molecule shows its inhibition of the chaperone function of 14-3-3s against other proteins, such kind of non-specific recognition ability with lysine residues might cause some side effects. Our simulations also suggest that the nearby environment of those lysine sites could largely affect these kinds of interactions via space hindrances or other factors. On the other hand, those molecules with structural characteristics of polar/non-polar inner cavity and opposite polarity outside show particular functions in the regulation of the protein functions. Our MD simulations of the supramolecular complexes formed by cycloaramide and cytochrome c suggested that only 2 of 18 surface exposed lysine residues could be effectively recognized (Pan et al., 2018). Much larger size of the macrocyclic molecule could be one of the reasons to cause this effect. Therefore, the possible direction of the inhibitor design to 14-3-3 proteins should not just consider the features of molecular cavity, but also the size of the inhibitor.
Small molecule regulation of PPI is currently one of the most promising and active fields in drug discovery and chemical biology. 14-3-3 proteins interact with hundreds of partner proteins and are involved in many physiological processes and diseases. Hence, strategies using small molecules to modulate these interactions have attracted extensive interests for years (Masters and Fu, 2001; Würtele et al., 2003; Ottmann et al., 2007a, 2009; Wu et al., 2010; Zhao et al., 2011; Arrendale et al., 2012; Bier et al., 2013; Thiel et al., 2013; Hartman and Hirsch, 2017; Ehlers et al., 2018; Stevers et al., 2018). One synthetic water-soluble belt-like supramolecular ligand, tweezer (CLR01), was specifically designed to inhibit the PPIs via strong binding affinity with those surface exposed lysine residues of 14-3-3σ. Therefore, in order to understand how the tweezer molecule regulates the interactions between 14-3-3σ and its partner proteins, the possible recognition behavior should be identified first.
We, in this work, systematically investigated the recognition ability of all surface lysine residues by the tweezer molecule using classical MD simulations and corresponding binding free energy calculations. A total 10 of 17 lysine residues were found to form the possible inclusion complexes with this inhibitor. Major contact comes from interactions between the long alkyl chain of lysine and the cavity formed by the norbornadiene and benzene rings of the tweezer molecule. In addition, the stable ion pair formed between the phosphate group of the inhibitor and positive charge residues on the surface of protein could provide additional contributions. Our simulation clearly indicates there is no preferential lysine recognition site for the tweezer molecule. We can locate all the possible binding sites either on the protein surface or at the dimeric interfacial region. Such recognition features might facilitate its function in the regulation of possible 14-3-3σ involved PPIs. On the other hand, this non-specific recognition could also cause unexpected side effects. Finally, to completely understand the effects of the inhibitor in the PPI, we have to include the second protein in our simulation, e.g., ExoS. Simulation work to this direction is underway in our lab.
MS and DX contributed conception and design of the study, and performed the statistical analysis, and wrote the manuscript. All authors contributed to manuscript revision, read and approved the submitted version.
This work was supported by National Key Research and Development Program (No. 2016YFB0700801) and National Science Foundation of China (No. 21473117).
Some of results described in this paper were obtained on the National Supercomputing Center of Guangzhou and Supercomputing Center of Sichuan University.
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Messaritou, G., Grammenoudi, S., and Skoulakis, E. M.C. (2010). Dimerization is essential for 14-3-3 zeta stability and function in vivo. J. Biol. Chem. 285, 1692–1700. doi: 10.1074/jbc.M109.045989.
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Copyright © 2019 Shi and Xu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.


Citation: LEUNG OI KAM, AEGEAN (2007-05-18). Human resource management in growing new ventures: Core team formation, core team characteristics and core team effects on employment models. ScholarBank@NUS Repository.
Abstract: This thesis contains three papers on the formation, composition, and effects of new venture core teams. Paper one, Different Ties for Different Needs - The Use of Networks in Core Team Recruitment in New Ventures examines how entrepreneurial firms use different types of network ties in acquiring their core team members at their startup and growth phases, taking into account varying environmental constraints, strategic needs, and inter-personal dynamics. Paper two, Ownership Imprinting on New Venture Team Formation and Composition examines effects of founding ownership structure on team hiring and team composition of young entrepreneurial firms, using imprinting mechanism as the key theoretical lens. Paper three, Change and Stability of Employment Models in Entrepreneurial Firms: The Dual Paths of Core Team Imprinting and Structural Inertia again draws on imprinting theory in examining how team composition and team stability affect the change paths of employment models from the startup to the growth phase.


text:
Reduce, Reuse, Recycle - The Bureaucratic Tear-Down & Assembling the Infrastructure Anew
By Aaron Anderson Aaron Anderson - Director of Strategic Organizational Initiatives at San Francisco State University, College of Business
Double Loop Learning
Reinvent the means of control
Enable communities of passion
Disaggregate the organization
The trouble with instigating, supporting and empowering communities of passion (CoP) is that the bureaucracies we created to establish organizations and make them successful, particularly after the agency has busted beyond a certain number of employees - say, arbitrarily 30 FTE, is that the architecture necessary to enable the growth of a company often suffocate it as it matures.
The problem this hack/solution addresses is one enabling the dismantling of old, decaying, or rigid bureaucratic infrastructure that stifle creative communities of passion to allow for new forms that enable CoP rather than asphyxiate them. Ask your self this one question: If we are really all about inventing new ways of managing, but still organize our operations in the same way (Board, C-Suite, mid-level, rank-and-file, etc), how can we expect the action of managing look any different?
What we need is not just frame breaking solutions, but we need to realized the architecture used to build a solid foundation may need to be disassembled, perhaps reduced, some portions reused, and others recycled into a new form. Effectively, in order continuously enable communities of passion, we need to the equivalent of an architectural tear down and rebuild, being careful to retain the DNA of the operation (or not), to craft an agile operation that is comfortable with periodic bouts of chaos in order to reinvent itself for a new era.
If you create an organization that regularly, and traditionally reconsiders the whole of it's back end infrastructure and basic architecture, you may enable it to become more comfortable and accustom to change such that the culture accepts, embraces, and even encourages change and the whole of the organization becomes used to the chaos such that they would be discomforted by the false security that stable periods instil. By regularly assessing the overall composition of the operation from the foundation up, and making it okay to reduce, reuse, or recycle portions of it, we may see organizations that have more malleable design structures such that permanence becomes foreign, and fluidity, ambiguity and dextrous responses to impinging market forces become friends rather than enemies of the operation.
This is essentially an expansion of Romanelli and Tushman's punctuated equilibrium theory and capitalizes on the notion that it's only in chaotic times that the most consequential change occurs.
Step one - Recognize you have a problem & that it rests in the very architecture that allowed you to become successful in the first place
Step two - Examine your status quo
Step Three - throw your existing organizational design to the wolves of change
Step Four - Embrace the chaos as your most creative time
Step Five - Work through it together
Step Six - Never cement the new status quo
Step Seven - Evaluate (ensuring the activation of double loop feedback cycles a la Chris Argyris), Rinse & Repeat
Hat tip to Romenelli and Tushman and their Punctuated Equilibrium Theory, and Chris Argyris the originator of double loop learning.
Also credit and hat tip to all my colleagues that have been collaborating in the Hackathon pilot group. Without the interacivity and discussion about communities of passion, this hack may never have been conjoured up.
Deborah Mills-Scofield Deborah Mills-Scofield
I am blessed to have 2 clients that do this regularly - both are private, both family businesses, 1 is 161yrs old, 1 is 60yrs old - 1 is led by a management team in their 40's-50's and 1 in their 20's-30's which demonstrates to me it's not age but mindset...the older company is the more fascinating to me because one wouldn't think they would rethink org structure since they've been incredibly successful - but that's their competitive advantage - they don't take success for granted and keep adapting and adopting to change - because as we know, the greatest barrier to success is....success. This is a great post - very hard to do - but very necessary
Aaron Anderson Aaron Anderson
Thanks for the comments Deborah.
Given that I work in an organization that is over 100 years old (SF State was founded in 1899), and in an industry that dates back to the dawn of the Colonies here in the USA (Harvard founded in 1636) and close to 4 or 5 centuries across the pond (Heidelberg, Cambridge, Oxford, etc...), we are both witness to orgs that must adapt and change, or die.
The problem now is exactly what you have put your finger on - particularly in higher education operations - because the US system of higher education has been highly successful, particularly as measured post the GI Bill and the mid-20th century, we have gotten ourselves into a bit of a rut - both in terms of infrastructure and bureaucratic structures. What's it going to take to get higher ed orgs to reduce, reuse, and recycle? Could be a tipping point is at hand.
I would be curious to know the industries your two orgs are in to get a sense of the kind of adaptation they have weathered.
Terri Griffith Terri Griffith
I like this idea, "Ask yourself these questions: if you were to topple over your current operation, tear down the foundation, and rebuild anew, would you build it up in exactly the same fashion? What would you reduce? What would you reuse? What would you recycle?" and actually suggest you open there. then shift the hack to focus on how you make decisions around your questions. Great opportunity to drill down.

redpajama_set_name: RedPajamaCommonCrawl


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