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Cooperability
| Project leader |
Zagrovic Bojan |
| Project co-leader: |
Gordan Žitković |
| Administering organization: |
Mediterranean Institute for Life Sciences, Split, Croatia |
| Partner Institution/Company: |
University of Texas at Austin, USA |
| Grant type: |
1A |
| Project title: |
Worldwide distributed computing in molecular biology: from dynamic activation of enzymes to the problem of conformational averaging in structure determination |
| Project summary: |
From proteins to nucleic acids, from lipids to carbohydrates, all biomolecules move, fluctuate and change structure. In fact, it is precisely their dynamics that provides a connection between structure and function. Despite the great advances on the experimental front, currently the only way to probe biomolecular dynamics on a single molecule level and with all-atom, femtosecond resolution is through computer simulations. The overarching theme of my proposal can be summarized as developing and applying theoretical and computational approaches to study biomolecular dynamics and its influence on our understanding of the structure-function relationship. In particular, I will focus on further developing and utilizing world-wide distributed computing methodologies ("grid computing") in studying biomolecular dynamics, and especially those aspects of it that are notoriously difficult to study experimentally.
First, I will focus on the role of protein dynamics, as manifested in its connections with the entropic component of the free energy change, in enzymatic activation. I will evaluate, utilize and develop different approaches founded on statistical mechanics to treat entropic contributions, and use them to attack fundamental questions in enzymology. The key hypothesis that I will examine is the possibility that enzymatic activation can occur in the absence of any conformational change, simply through redistribution of dynamics around the same average structure. Second, I will probe the issues of conformational averaging in structural experiments on biomolecules. Biomolecular 3D structures are models built upon highly averaged signals coming from often very dynamic and diverse molecular ensembles. This averaging may, in fact, select and affirm certain structural features which are observed in a macroscopic experiment and then erroneously attributed to the properties of the molecules themselves. I will be using atomistic models to generate and manipulate different microscopic ensembles which are consistent with given averaged experimental observables, and then look for rigorous ways of determining their quality and informational content.
Overall, my ambition is to use large-scale computing to help move biosimulations to a level where they will be a quality, powerful partner to experiment in analyzing realistic biomolecules on realistic timescales in realistic environments.
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| Hrvatski sažetak: |
Globalno raspodijeljeno računarstvo u molekularnoj biologiji: od dinamičke aktivacije enzima do problema konformacijskog usrednjavanja u određivanju struktura.
Od proteina do nukleinskih kiselina, od lipida do ugljikohidrata, sve biomolekule se kreću, fluktuiraju i mijenjaju strukturu. Bez obzira na značajne pomake na strani eksperimentalnih metoda, trenutno jedini način za istraživanje biomolekularne dinamike na razini pojedinačnih atoma i uz femtosekundnu rezoluciju je uz pomoć računarskih simulacija.
Središnja tema projekta je razvijanje i primjena teorijskih i računarskih pristupa za proučavanje biomolekularne dinamike i utjecaja koji ona ima na naše razumijevanje odnosa strukture i funkcije. Razvijat će se i primjenjivati raspodijeljeno računanja na internetskoj mreži („grid computing“) u proučavanju biomolekularne dinamike.
Cilj je projekta koristiti najmodernije računarske tehnike s najvećim resursima kako bi se biosimulacije podigle na razinu na kojoj će biti kvalitetan partner eksperimentima u proučavanju realističnih biomolekula na realističnim vremenskim skalama u realističnim okolišima.
Boris Žagrović znanstveni je direktor i voditelj istraživačke grupe na Mediteranskom institutu za istraživanje života u Splitu. Diplomirao je biokemiju na Sveučilištu Harvard, a doktorirao biofiziku na Sveučilištu Stanford u SAD-u. U Hrvatsku se vratio 2007. nakon rada na ETH u Zürichu. Stučnjak je za računalne simulacije bioloških problema.
Gordan Žitković izvanredni je profesor na University of Texas at Austin, diplomirao je matematiku na Sveučilištu u Zagrebu a doktorirao na Sveučilištu Columbia u New Yorku. Stručnjak je za teoriju vjerojatnosti. |
| Amount requested from UKF: |
198.402 € |
| Amount of matching funding: |
90.000 € |
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