Independent Markov Decomposition: Towards modeling kinetics of biomolecular complexes

Abstract

In order to advance the mission of in silico cell biology, modeling the interactions of large and complex biological systems becomes increasingly relevant. The combination of molecular dynamics (MD) and Markov state models (MSMs) have enabled the construction of simplified models of molecular kinetics on long timescales. Despite its success, this approach is inherently limited by the size of the molecular system. With increasing size of macromolecular complexes, the number of independent or weakly coupled subsystems increases, and the number of global system states increase exponentially, making the sampling of all distinct global states unfeasible. In this work, we present a technique called Independent Markov Decomposition (IMD) that leverages weak coupling between subsystems in order to compute a global kinetic model without requiring to sample all combinatorial states of subsystems. We give a theoretical basis for IMD and propose an approach for finding and validating such a decomposition. Using empirical few-state MSMs of ion channel models that are well established in electrophysiology, we demonstrate that IMD can reproduce experimental conductance measurements with a major reduction in sampling compared with a standard MSM approach. We further show how to find the optimal partition of all-atom protein simulations into weakly coupled subunits.

Fitting Side-Chain NMR Relaxation Data Using Molecular Simulations

“…One potential way forward might be to create (structurally) local models of the dynamics (to overcome the high dimensionality of the problem) and then reconstruct models of the full protein dynamics from these. 61,62 As reweighting methods such as ABSURDer rely on an overlap between experiment and calculated parameters prior to reweighting, they are aided by good agreement before reweighting. 42,51,63 Indeed, the extent of reweighting needed to obtain good agreement is related to a measure of the error in the force field.…”

“…This likely arises because many side-chain motions are only weakly and locally coupled and that any potential long-range coupling could arise from these local effects. − In addition to using simulation-derived correlation functions, the ABSURDer approach differs from standard methods for analyzing NMR relaxation data by aiming to fit the dynamics of all residues at the same time. One potential way forward might be to create (structurally) local models of the dynamics (to overcome the high dimensionality of the problem) and then reconstruct models of the full protein dynamics from these. , …”

Fitting side-chain NMR relaxation data using molecular simulations

“…In addition to using simulation-derived correlation functions, the ABSURDer approach differs from standard methods for analysing NMR relaxation data by aiming to fit the dynamics of all residues at the same time. One potential way forward might be to create (structurally) local models of the dynamics (to overcome the high-dimensionality of the problem) and then reconstruct models of the full protein dynamics from these ( Olsson and Noé, 2019 ; Hempel et al, 2021 ).…”