RESEARCH

[Protein folding and design]  |  [Molecular Evolution]  |  [Drug Discovery]

Protein Folding and Design

The unifying theme of this subgroup is the quest to understand physical and evolutionary principles that govern folding of proteins into their unique biologically active structure. We developed a variety of approaches - from analytical theory of random and evolutionary selected heteropolymers to lattice and other simplified models to all-atom simulations with fully transferable potentials. Our group discovered universal physical requirements for polypeptide chains to fold into unique structure (energy gap criterion), uncovered universal kinetic mechanism of protein folding that dominates present understanding of protein folding kinetics (nucleation scenario) and showed deep connection between physical mechanism of protein folding and evolutionary selection of sequences (phenomenon of ''Conservation of Conservation''). More recently we developed new approaches to high-resolution protein folding that, for the first time, allowed all atom ab initio folding of structurally diverse proteins into their native conformations that are global minima of energy. This is achieved due to development of new fully transferable all-atom potential for protein folding. In the future we plan to build on these development to work towards complete understanding of protein folding mechanism(s) at atomic level of detail and fully automated methods to predict protein structure from sequences in ab initio simulations.

Molecular Evolution

Research of this subgroup is aimed at understanding general physical and biological principles that drive evolution of Protein Universe and Protein-Protein Interactions. We developed a new graph-theoretical approach to global analysis of protein fold universe and found its highly nonrandom, scale-free organization indicative of specific evolutionary processes that lead to its creation. The divergent scenario (''Big Bang'' model) provided deep insights into origin of new folds, mechanism of speciation and provided new, structure-based approach to phylogeny - building ''tree of life''. Thinking along these lines we discovered specific mechanisms of thermophilic adaptation, in the context of evolutionary history of organisms. Our present efforts are aimed at development of molecular theory of Darwinian evolution that would combine precision and accuracy of current understanding of physical mechanisms of protein stability and function with realistic description of evolutionary pressures that occur at the level of organisms and populations. In a related set of more recent projects we started to uncover how specific protein-protein interactions evolved under positive and negative design selective pressures.

Drug Discovery

Our approach to drug discovery effort is based on the quest to understand physical chemistry of protein-small molecule interactions that determine their specificity. Along these lines we developed a new algorithm, CombiSMoG that builds new molecules that bind to specific sites of protein targets. Efficiency of CombiSMoG has been demonstrated in design of novel recored binding inhibitors for a known enzyme (Carbonic Anhydrase). We work now on development of new generation of the theory and algorithm that will design better (more drug-like) molecules, will predict their affinities with greater accuracy and take into account protein flexibility and need to enhance specificity (reduce side-effect binding).

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