Water is an essential mediator of protein-ligand interactions; however, whether or not such water molecules are critical for the progress of ligand dissociation remains unclear. To gain a more complete understanding, we performed molecular dynamics simulations using rigid model binding sites and trypsin-benzamidine. The results of two-dimensional free-energy landscape provided clear view of water-ligand exchange process; two different mechanisms appear depending on whether the binding site is buried or not. As the site is more buried, water access is more difficult. When water does not access the site, ligand dissociation produces a large energy barrier, i.e., slow dissociation kinetics. This indicates that control of ligand dissociation kinetics becomes possible with burying the binding site. Yet, appropriate burying is important because burying reduces not only water access but also ligand binding. We also discuss the role of protein structural change; it likely plays a similar role to water access because during ligand dissociation, it can make new coordination with the ligand binding site like water. These results contribute to the future pharmaceutical drug design and will be useful for fundamental exploration of various molecular events.

Microscopic relationship between water access and protein-ligand dissociation

ACS Fall 2021

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