Flexible Gaussian Accelerated Molecular Dynamics to Enhance Biological Sampling

Abstract

Molecular dynamics simulations often struggle to obtain sufficient sampling to study complex molecular events due to high energy barriers separating the minima of interest. Multiple enhanced sampling techniques have been developed and improved over the years to tackle this issue. Gaussian accelerated molecular dynamics (GaMD) is a recently developed enhanced sampling technique that works by adding a biasing potential, lifting the energy landscape up, and decreasing the height of its barriers. GaMD allows one to increase the sampling of events of interest without the need of a priori knowledge of the system or the relevant coordinates. All required acceleration parameters can be obtained from a previous search run. Upon its development, several improvements for the methodology have been proposed, among them selective GaMD in which the boosting potential is selectively applied to the region of interest. There are currently four selective GaMD methods that have shown promising results. However, all of these methods are constrained on the number, location, and scenarios in which this selective boosting potential can be applied to ligands, peptides, or protein−protein interactions. In this work, we showcase a GROMOS implementation of the GaMD methodology with a fully flexible selective GaMD approach that allows the user to define, in a straightforward way, multiple boosting potentials for as many regions as desired. We show and analyze the advantages of this flexible selective approach on two previously used test systems, the alanine dipeptide and the chignolin peptide, and extend these examples to study its applicability and potential to study conformational changes of glycans and glycosylated proteins.

Computer-Aided Tunnel Engineering: A Promising Strategy for Improving Lipase Applications in Esterification Reactions

“…It works by adding a harmonic boost potential to smooth the biomolecular potential energy surface and reduce energy barriers. Without the need to set predefined reaction coordinates or collective variables, GaMD provides unconstrained enhanced sampling and is advantageous for simulating complex biological processes. , Additionally, SMD is a special type of MD simulations and applies a directional vector to a molecule or protein in order to study how it responds to external forces . SMD simulations are widely used to study many biophysical processes, including the (un)­folding mechanism of proteins .…”