Abstract:

Human serum albumin (HSA) is an extracellular protein that has the highest concentration in blood plasma and is a carrier for many small molecules. HSA has an exceptional binding capacity for many endogenous and exogenous ligands, and contains two main binding sites with high affinity for diverse substances, named Site Ⅰ and Site Ⅱ. The binding cavity of Site Ⅱ is more active and has greater ligand affinity than that of Site Ⅰ. In this study, molecular simulation methods were used to investigate the molecular interactions between Site Ⅱ and twelve Site Ⅱ-specific ligands. The results showed that hydrophobic interactions were the main driving force for binding, with electrostatic interactions playing a secondary role. The key residues and binding mode on Site Ⅱ were identified with the computational alanine-scanning approach. Three layers were found from the entrance to the interior of the binding pocket, contributing electrostatic interactions, hydrophobic interactions and mixed interactions, respectively. Finally, molecular docking and molecular dynamics were used to predict the binding mode of L-tryptophan on Site Ⅱ. The results provided insights into the binding mode of Site Ⅱ on HSA, which could guide the design of new Site Ⅱ-specific drugs and ligands for the efficient separation of HSA.

Key words: Human serum albumin, Site Ⅱ, Molecular docking, Molecular dynamics, Binding mode