Advances in enhanced sampling along adaptive paths of collective variables

Abstract

Study of complex activated molecular transitions by molecular dynamics (MD) simulation can be a daunting task, especially when little knowledge is available on the reaction coordinate describing the mechanism of the process. Here, we assess the path-metadynamics enhanced sampling approach in combination with force field and [density functional theory (DFT)] MD simulations of conformational and chemical transitions that require three or more collective variables (CVs) to describe the processes. We show that the method efficiently localizes the average transition path of each process and simultaneously obtains the free energy profile along the path. The new multiple-walker implementation greatly speeds-up the calculation, with an almost trivial scaling of the number of parallel replicas. Increasing the dimensionality by expanding the set of CVs leads to a less than linear increase in the computational cost, as shown by applying the method to a conformational change in increasingly longer polyproline peptides. Combined with DFT-MD to model acid (de-)protonation in explicit water solvent, the transition path and associated free energy profile were obtained in less than 100 ps of simulation. A final application to hydrogen fuel production catalyzed by a hydrogenase enzyme showcases the unique mechanistic insight and chemical understanding that can be obtained from the average transition path.

Frontiers in Multiscale Modeling of Photoreceptor Proteins

“…Examples of this kind of methods can be found in Refs (112‐114). The benefits are three‐fold: (1) free energy calculations along adaptive paths are not subject to the exponential increase in cost with the dimensionality of the reaction coordinate, and can reach a linear performance scaling (115); (2) with the diminished penalty for dimensionality, one can introduce more candidate CVs in a single attempt to increase the chance of success; and (3) with the directionality provided by the path, the sampling is focused into the transition region of interest. Furthermore, most standard biasing methods (e.g., umbrella sampling (116) or metadynamics (117)) and algorithmic extensions can be employed either along the path (118), or in the direction perpendicular to it in order to find alternative mechanisms (119).…”

Closer Look at Inverse Electron Demand Diels–Alder and Nucleophilic Addition Reactions on s-Tetrazines Using Enhanced Sampling Methods

“…The path-CV developed by Branduardi et al [71] is another possible choice for a CV. The path-CV has been used to study complex chemical systems and calculate their associated FESs [72][73][74], allowing one to compute the progress along the highdimensional reaction path R and the distance Z( ) from the (high-dimensional) reference path (see Fig. 4).…”

Hydration interactions beyond the first solvation shell in aqueous phenolate solution

“…To investigate the aqueous solvation structure and dynamics of phenolate in more detail, we perform DFT-MD simulations of phenolate and phenol solutions. DFT-MD simulations have been shown to accurately model the aqueous solvation of small solutes [69][70][71] and to predict the anisotropy decay of water in such solutions reasonably well. 36 Fig.…”