Protein-Ligand Binding process is ubiquitous in biological systems. The reaction rate is mainly determined from the approaching process of ligand to receptor protein (diffusion) and insertion process. Recently, ligand binding process has been extensively investigated by means of microsecond-scale molecular dynamics (MD) simulation. These previous works focus on the reaction in diluted systems. However, in biological systems, both protein and ligand molecules are surrounded by other proteins and metabolites referred to as crowded environments, and hence the reaction is strongly affected by them. In the present study, we elucidate the crowder effect on ligand-binding process based on MD simulation. The target receptor protein and ligand molecule are Src kinase and PP1 inhibitor, respectively. The kinase has many binding sites, in addition to the canonical binding site. Eight Bovine serum albumin (BSA) protein molecules are placed in the system as crowder. We found that the large portion of the ligand molecules are trapped by the crowder protein surfaces, corresponding to the decreasing of the ligand concentration around the kinase. At the same time, the spatial density distribution (SDF) analysis for the ligands indicates that the many binding sites of the kinase is sterically blocked by the crowder. We also found that the approching of the ligands to the kinase via the surface of the crowder molecules often occurs, meaning that the approaching pathway is significantly changed from that in dilute system.

Elucidating the crowding effect on protein-ligand binding process

2019 Spring National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.