Theory And Simulation Of Protein Dynamics, Folding, And

Diabetes, Digestive, Kidney Diseases

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Abstract

We have made significant progress in three major areas related to protein dynamics, folding, and function. (1) Water and proton transport through molecular channels and biomolecular proton pumping. We succeeded in simulating the osmotically-driven flow of water through subnanometer pores in a membrane of nanotubes, providing new insights into transmembrane water transport through water pores such as aquaporin-1. We could also show that one-dimensionally ordered water chains formed inside nonpolar channels are excellent conductors of protons. Based on these results, we demonstrated how the unique properties of water in narrow pores are exploited in the biological proton pump cytochrome c oxidase to couple redox chemistry (O2 + 4H+ + 4e- -> 2H2O) to vectorial transfer of four protons across the mitochondrial or bacterial membrane. Together with protein dynamics, water chains also play a central role in enzyme catalysis of cytochrome P450. (2) Protein and peptide folding. To address one of the main challenges in molecular simulations, the time-scale problem, we have developed a "coarse molecular dynamics" formalism in which the information from multiple short trajectories is used to extrapolate to the long-time dynamics, to map free energy surfaces, and to explore the configuration space efficiently. (3) Theory of single-molecule force spectroscopy experiments using atomic force microscopes or laser tweezers. We have developed and tested a theory for extracting kinetic rates from single-molecule pulling measurements, and applied the theory to the forced unfolding of the muscle-protein titin.