title: Probing the binding site characteristics of HSA: a combined molecular dynamics and cheminformatics investigation.
abstract: Human serum albumin is a remarkable protein found in high concentrations in the body. It contains at least seven distinct fatty acid binding sites and two principle sites for drugs. Its primary function is to act as a fatty acid transport system, but it also shows the capacity to bind a diverse range of acidic, neutral and zwitterionic drug molecules. In this paper we investigate the ligand binding selectivity of HSA using cheminformatics analyses and molecular dynamics simulations. We compare and contrast the known ligand binding specificities as obtained from X-ray structural data using PCA, with additional direct analyses of the seven key binding pockets using analyses derived from molecular simulations. We assess both the fatted and defatted states of HSA using 100 ns simulations of the APO and HOLO forms, as well as structures containing one, three and seven myristic acid molecules. We find that differences in fatty acid binding can have a dramatic effect on the flexibility of the protein and also the pocket characteristics. We discuss how the remarkable selectivity of the HSA pockets towards both endogenous fatty acids and exogenous drug molecules is not simply controlled by bulk property effects such as ionization state and lipophilicity.
authors.affiliation: Department of Chemistry, Faculty of Science, Kasetsart University, 50 Ngam Wong Wan Rd, Chatuchak, Bangkok 10900, Thailand.
authors.forename: Prapasiri
authors.initials: P
authors.lastname: Pongprayoon
authors.affiliation: Department of Chemistry, Faculty of Science, Kasetsart University, 50 Ngam Wong Wan Rd, Chatuchak, Bangkok 10900, Thailand. Electronic address: paul.gleeson@ku.ac.th.
authors.forename: M Paul
authors.initials: MP
authors.lastname: Gleeson
mesh_terms: D001665:Binding Sites; D006801:Humans; D056004:Molecular Dynamics Simulation; D009961:Orosomucoid / Q000737:chemistry; D025341:Principal Component Analysis; D011487:Protein Conformation; D012709:Serum Albumin / Q000737:chemistry*
chemical_list: D009961:Orosomucoid; D012709:Serum Albumin
keywords: Human serum albumin ADMET; Molecular dynamics (MD); Principal components analysis (PCA)