Development of Generalized-Ensemble Algorithms and their Application in Protein Studies

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Ulrich Hansmann of the University of Oklahoma is supported by the Chemical Theory, Models and Computational Methods program in the Chemistry Division to develop theoretical and computational approaches aimed at overcoming limitations of generalized-ensemble and replica-exchange techniques in protein folding studies. For this purpose, the replica exchange protocol is reformulated to enable its efficient use in multiscale and explicit solvent simulations; and an automatic procedure is established for designing ensembles that maximize the sampling of folding/unfolding transitions. These techniques are then used to explore the utility of a multi-funnel concept for describing the role of mutations, changes in environment, or interaction with other molecules on protein folding. For this purpose, mutation-induced changes in the folding landscape of the A and B domain of protein G and the inter-conversion between the two functional forms of lymphotactin are studied. The project aims at overcoming sampling difficulties that hold back the use of atomistic molecular dynamics or Monte Carlo simulations for complementing experiments in exploring the molecular machinery of cells. New techniques are developed and applied to study the folding mechanism of especially interesting proteins, in order to obtain a more complete view of protein folding and cellular processes. In order to broaden the impact of the project an annual workshop "From Computational Biophysics to Systems Biology" is organized; and summer internships are offered to undergraduate students from diverse backgrounds.