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J Chem Phys. 2017 Oct 21;147(15):152725. doi: 10.1063/1.5004774.

Peptide dimerization-dissociation rates from replica exchange molecular dynamics.

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School of Physics, University College Dublin, Belfield, Dublin 4, Ireland.
Department of Chemistry, King's College London, London SE1 1DB, United Kingdom.
Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Max-von-Laue-Stra├če 3, 60438 Frankfurt am Main, Germany.


We show how accurate rates of formation and dissociation of peptide dimers can be calculated using direct transition counting (DTC) from replica-exchange molecular dynamics (REMD) simulations. First, continuous trajectories corresponding to system replicas evolving at different temperatures are used to assign conformational states. Second, we analyze the entire REMD data to calculate the corresponding rates at each temperature directly from the number of transition counts. Finally, we compare the kinetics extracted directly, using the DTC method, with indirect estimations based on trajectory likelihood maximization using short-time propagators and on decay rates of state autocorrelation functions. For systems with relatively low-dimensional intrinsic conformational dynamics, the DTC method is simple to implement and leads to accurate temperature-dependent rates. We apply the DTC rate-extraction method to all-atom REMD simulations of dimerization of amyloid-forming NNQQ tetrapetides in explicit water. In an assessment of the REMD sampling efficiency with respect to standard MD, we find a gain of more than a factor of two at the lowest temperature.

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