Water regulates the residence time of Benzamidine in Trypsin

TL;DR

This study uses advanced simulations and machine learning to explore how water molecules influence the unbinding process of Benzamidine from Trypsin, providing insights consistent with experimental data.

Contribution

It introduces a novel approach combining enhanced sampling and machine learning to quantify water's role in ligand unbinding dynamics.

Findings

Water molecules facilitate ligand release via hydrogen bond networks.

Presence of specific water molecules modulates unbinding times.

Simulation results align well with experimental observations.

Abstract

The process of ligand-protein unbinding is crucial in biophysics. Water is an essential part of any biological system and yet, many aspects of its role remain elusive. Here, we simulate with state-of-the-art enhanced sampling techniques the binding of Benzamidine to Trypsin which is a much studied and paradigmatic ligand-protein system. We use machine learning methods to determine efficient collective coordinates for the complex non-local network of water. These coordinates are used to perform On-the-fly Probability Enhanced Sampling simulations, which we adapt to calculate also the ligand residence time. Our results, both static and dynamic, are in good agreement with experiments. We find that the presence of a water molecule located at the bottom of the binding pocket allows via a network of hydrogen bonds the ligand to be released into the solution. On a finer scale, even when unbinding is allowed, another water molecule further modulates the exit time.