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.
| Rosta, Edina; Buchete, Nicolae-Viorel; Hummer, Gerhard (2009) Thermostat artifacts in replica exchange molecular dynamics simulations. J Chem Theory Comput 5:1393-1399 |
| Best, Robert B; Hummer, Gerhard (2009) Biochemistry. Unfolding the secrets of calmodulin. Science 323:593-4 |
| Tikhonova, Irina G; Best, Robert B; Engel, Stanislav et al. (2008) Atomistic insights into rhodopsin activation from a dynamic model. J Am Chem Soc 130:10141-9 |
| Turjanski, Adrian Gustavo; Gutkind, J Silvio; Best, Robert B et al. (2008) Binding-induced folding of a natively unstructured transcription factor. PLoS Comput Biol 4:e1000060 |
| Kim, Young C; Tang, Chun; Clore, G Marius et al. (2008) Replica exchange simulations of transient encounter complexes in protein-protein association. Proc Natl Acad Sci U S A 105:12855-60 |
| Best, Robert B; Buchete, Nicolae-Viorel; Hummer, Gerhard (2008) Are current molecular dynamics force fields too helical? Biophys J 95:L07-9 |
| Buchete, Nicolae-Viorel; Hummer, Gerhard (2008) Peptide folding kinetics from replica exchange molecular dynamics. Phys Rev E Stat Nonlin Soft Matter Phys 77:030902 |
| Buchete, Nicolae-Viorel; Hummer, Gerhard (2008) Coarse master equations for peptide folding dynamics. J Phys Chem B 112:6057-69 |
| Kim, Young C; Hummer, Gerhard (2008) Coarse-grained models for simulations of multiprotein complexes: application to ubiquitin binding. J Mol Biol 375:1416-33 |
| Canagarajah, Bertram J; Hummer, Gerhard; Prinz, William A et al. (2008) Dynamics of cholesterol exchange in the oxysterol binding protein family. J Mol Biol 378:737-48 |
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