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J Chem Phys. 2018 Aug 21;149(7):072323. doi: 10.1063/1.5027580.

Conformational analysis of replica exchange MD: Temperature-dependent Markov networks for FF amyloid peptides.

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School of Physics, University College Dublin, Belfield, Dublin 4, Ireland.
Laboratory of Computational Biology, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, USA.


Recent molecular modeling methods using Markovian descriptions of conformational states of biomolecular systems have led to powerful analysis frameworks that can accurately describe their complex dynamical behavior. In conjunction with enhanced sampling methods, such as replica exchange molecular dynamics (REMD), these frameworks allow the systematic and accurate extraction of transition probabilities between the corresponding states, in the case of Markov state models, and of statistically-optimized transition rates, in the case of the corresponding coarse master equations. However, applying automatically such methods to large molecular dynamics (MD) simulations, with explicit water molecules, remains limited both by the initial ability to identify good candidates for the underlying Markovian states and by the necessity to do so using good collective variables as reaction coordinates that allow the correct counting of inter-state transitions at various lag times. Here, we show that, in cases when representative molecular conformations can be identified for the corresponding Markovian states, and thus their corresponding collective evolution of atomic positions can be calculated along MD trajectories, one can use them to build a new type of simple collective variable, which can be particularly useful in both the correct state assignment and in the subsequent accurate counting of inter-state transition probabilities. In the case of the ubiquitously used root-mean-square deviation (RMSD) of atomic positions, we introduce the relative RMSD (RelRMSD) measure as a good reaction coordinate candidate. We apply this method to the analysis of REMD trajectories of amyloid-forming diphenylalanine (FF) peptides-a system with important nanotechnology and biomedical applications due to its self-assembling and piezoelectric properties-illustrating the use of RelRMSD in extracting its temperature-dependent intrinsic kinetics, without a priori assumptions on the functional form (e.g., Arrhenius or not) of the underlying conformational transition rates. The RelRMSD analysis enables as well a more objective assessment of the convergence of the REMD simulations. This type of collective variable may be generalized to other observables that could accurately capture conformational differences between the underlying Markov states (e.g., distance RMSD, the fraction of native contacts, etc.).

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