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MSM/RD: Coupling Markov state models of molecular kinetics with reaction-diffusion simulations

  • Molecular dynamics (MD) simulations can model the interactions between macromolecules with high spatiotemporal resolution but at a high computational cost. By combining high-throughput MD with Markov state models (MSMs), it is now possible to obtain long-timescale behavior of small to intermediate biomolecules and complexes. To model the interactions of many molecules at large lengthscales, particle-based reaction-diffusion (RD) simulations are more suitable but lack molecular detail. Thus, coupling MSMs and RD simulations (MSM/RD) would be highly desirable, as they could efficiently produce simulations at large time- and lengthscales, while still conserving the characteristic features of the interactions observed at atomic detail. While such a coupling seems straightforward, fundamental questions are still open: Which definition of MSM states is suitable? Which protocol to merge and split RD particles in an association/dissociation reaction will conserve the correct bimolecular kinetics and thermodynamics? In this paper, we make the first step towards MSM/RD by laying out a general theory of coupling and proposing a first implementation for association/dissociation of a protein with a small ligand (A + B <--> C). Applications on a toy model and CO diffusion into the heme cavity of myoglobin are reported.

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Author:Manuel Dibak, Mauricio J. del Razo, David De Sancho, Christof Schütte, Frank Noé
Document Type:Article
Parent Title (English):Journal of Chemical Physics
Year of first publication:2018
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