Short-Time Infrequent Metadynamics for Improved Kinetics Inference.

Abstract

Infrequent Metadynamics is a popular method to obtain the rates of long time-scale processes from accelerated simulations. The inference procedure is based on rescaling the first-passage times of the Metadynamics trajectories using a bias-dependent acceleration factor. While useful in many cases, it is limited to Poisson kinetics, and a reliable estimation of the unbiased rate requires slow bias deposition and prior knowledge of efficient collective variables. Here, we propose an improved inference scheme, which is based on two key observations: (1) the time-independent rate of Poisson processes can be estimated using short trajectories only. (2) Short trajectories experience minimal bias, and their rescaled first-passage times follow the unbiased distribution even for relatively high deposition rates and suboptimal collective variables. Therefore, by basing the inference procedure on short time scales, we obtain an improved trade-off between speedup and accuracy at no additional computational cost, especially when employing suboptimal collective variables. We demonstrate the improved inference scheme for a model system and two molecular systems.