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

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.