All-atom molecular dynamics (MD) simulations offer a highly detailed, specific, and yet inherently limited tool for understanding the dynamics of biomolecules. In particular, time-scale limitations currently prevent MD from providing the full spectrum of conformational flexibility and complex organization available to any given protein or set of proteins and ligands when given only static structures as initial conditions. In this talk, I will describe recent work out of our group in which all-atom MD systems are augmented with collective variables in an attempt to characterize the thermodynamics of these systems using these variables. I will show applications of both temperature-acceleration and the string method in collective variables, and explain some technical aspects of their implementation for large-scale simulations. Focus will be on large-scale conformational sampling of the GroEL chaperonin subunit and HIV-1 gp120 and prediction of the mechanism of the native-to-amyloidogenic transition of beta2-microglobulin, as examples. I will conclude by considering what still lay in the future of all-atom simulations that will contribute to our understanding of the molecular basis of biological processes.
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