Affinity, Kinetics, and Pathways of Anisotropic Ligands Binding to Hydrophobic Model Pockets

TL;DR

This study uses molecular dynamics simulations to explore how chemical and shape anisotropy of small ligands affect their binding affinity, kinetics, and pathways to hydrophobic pockets, revealing the role of hydration and ligand orientation.

Contribution

It provides new insights into how ligand anisotropy influences binding mechanisms, kinetics, and pathways in hydrophobic pockets, highlighting the importance of hydration and orientation dynamics.

Findings

Hydrophobic sections are desolvated upon binding, guiding orientation via hydrophobic torque.

Ligands with bimodal orientation fluctuations face higher kinetic barriers.

Kinetic barriers vary significantly among different ligands, affecting binding and unbinding times.

Abstract

Using explicit-water molecular dynamics (MD) simulations of a generic pocket-ligand model we investigate how chemical and shape anisotropy of small ligands influences the affinities, kinetic rates and pathways for their association to hydrophobic binding sites. In particular, we investigate aromatic compounds, all of similar molecular size, but distinct by various hydrophilic or hydrophobic residues. We demonstrate that the most hydrophobic sections are in general desolvated primarily upon binding to the cavity, suggesting that specific hydration of the different chemical units can steer the orientation pathways via a `hydrophobic torque'. Moreover, we find that ligands with bimodal orientation fluctuations have significantly increased kinetic barriers for binding compared to the kinetic barriers previously observed for spherical ligands due to translational fluctuations. We exemplify that these kinetic barriers, which are ligand specific, impact both binding and unbinding times for which we observe considerable differences between our studied ligands.