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Accelerated Estimation of Long-Timescale Kinetics from Weighted Ensemble Simulation via Non-Markovian "Microbin" Analysis.

ABSTRACT: The weighted ensemble (WE) simulation strategy provides unbiased sampling of nonequilibrium processes, such as molecular folding or binding, but the extraction of rate constants relies on characterizing steady-state behavior. Unfortunately, WE simulations of sufficiently complex systems will not relax to steady state on observed simulation times. Here, we show that a postsimulation clustering of molecular configurations into "microbins" using methods developed in the Markov State Model (MSM) community can yield unbiased kinetics from WE data before steady-state convergence of the WE simulation itself. Because WE trajectories are directional and not equilibrium distributed, the history-augmented MSM (haMSM) formulation can be used, which yields the mean first-passage time (MFPT) without bias for arbitrarily small lag times. Accurate kinetics can be obtained while bypassing the often prohibitive convergence requirements of the nonequilibrium weighted ensemble. We validate the method in a simple diffusive process on a two-dimensional (2D) random energy landscape and then analyze atomistic protein folding simulations using WE molecular dynamics. We report significant progress toward the unbiased estimation of protein folding times and pathways, though key challenges remain.

SUBMITTER: Copperman J

PROVIDER: S-EPMC8045600 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The flavoenzyme monomeric sarcosine oxidase (MSOX) catalyzes a complex set of reactions currently lacking a consensus mechanism. A key question that arises in weighing competing mechanistic models of MSOX function is to what extent ingress of O2 from the solvent (and its egress after an unsuccessful oxidation attempt) limits the overall catalytic rate. To address this question, we have applied to the MSOX/O2 system the relatively new simulation method of Markovian milestoning molecular dynamics simulations, which, as we recently showed [ Yu et al. J. Am. Chem. Soc. 2015 , 137 , 3041 ], accurately predicted the entry and exit kinetics of CO in myoglobin. We show that the mechanism of O2 entry and exit, in terms of which possible solvent-to-active-site channels contribute to the flow of O2, is sensitive to the presence of the substrate-mimicking competitive inhibitor 2-furoate in the substrate site. The second-order O2 entry rate constants were computed to be 8.1 × 10(6) and 3.1 × 10(6) M(-1) s(-1) for bound and apo MSOX, respectively, both of which moderately exceed the experimentally determined second-order rate constant of (2.83 ± 0.07) × 10(5) M(-1) s(-1) for flavin oxidation by O2 in MSOX. This suggests that the rate of flavin oxidation by O2 is likely not strongly limited by diffusion from the solvent to the active site. The first-order exit rate constants were computed to be 10(7) s(-1) and 7.2 × 10(6) s(-1) for the apo and bound states, respectively. The predicted faster entry and slower exit of O2 for the bound state indicate a longer residence time within MSOX, increasing the likelihood of collisions with the flavin isoalloxazine ring, a step required for reduction of molecular O2 and subsequent reoxidation of the flavin. This is also indirectly supported by previous experimental evidence favoring the so-called modified ping-pong mechanism, the distinguishing feature of which is an intermediate complex involving O2, the flavin, and the oxidized substrate simultaneously in the cavity. These findings demonstrate the utility of the Markovian milestoning approach in contributing new understanding of complicated enyzmatic function.

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Accelerated Estimation of Long-Timescale Kinetics from Weighted Ensemble Simulation via Non-Markovian "Microbin" Analysis.

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