Describing Protein Folding Kinetics by Molecular Dynamics Simulations: II. Application to a beta-Hairpin Peptide

A rigorous formalism for the extraction of state-to-state transition functions from a Boltzmann-weighted ensemble of constant energy molecular dynamics (MD) simulations has been developed as a way to study the kinetics of protein folding in the context of a Markov chain. The method has been applied to the folding of the C-terminal beta-hairpin motif from protein G. In this work,states were defined suing a scheme where all possible native hydrogen bonding patterns could be resolved. Boltzmann weighted starting states produced by a replica exchange Monte Carlo procedure were used to perform 287 all-atom, explicit solvent microcanonical trajectories with an aggregate simulation time of approximately 120 nanoseconds. Markovian behavior was not observed, perhaps due to our choice of state definitions and the length of the simulations. The use of different criteria for the existence of a hydrogen bond results in the apparent observation of different mechanisms from the same underlying data: one set of criteria indicate a zipping type of process, but another indicates more of a collapse followed by almost simultaneous formation of a large number of contacts. Analysis of long-lived states observed during the simulations of the beta-hairpin suggests that important aspects of the folding process that are not captured by order parameters in common use include the formation of non-native hydrogen bonds and the degree and nature of salt bridge formation.

By: William C. Swope, Jed W. Pitera, Frank Suits, Mike Pitman, Maria Eleftheriou, Blake G. Fitch, Robert S. Germain, Aleksandr Rayshubski, T. J. C. Ward, Yuriy Zhestkov, Ruhong Zhou

Published in: Journal of Physical Chemistry B , volume 108, (no 21), pages 6582-94 in 2004

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