Five-nanosecond molecular dynamics (MD) simulations were performed on human serum albumin (HSA) to study the conformational features of its primary ligand binding sites (I and II). Additionally, 11 HSA snapshots were extracted every 0.5 ns to explore the binding affinity (Kd) of 94 known HSA binding drugs using a blind docking procedure. MD simulations indicate that there is considerable flexibility for the protein, including the known sites I and II. Movements at HSA sites I and II were evidenced by structural analyses and docking simulations. The latter enabled the study and analysis of the HSA–ligand interactions of warfarin and ketoprofen (ligands binding to sites I and II, respectively) in greater detail. Our results indicate that the free energy values by docking (Kd observed) depend upon the conformations of both HSA and the ligand. The 94 HSA–ligand binding Kd values, obtained by the docking procedure, were subjected to a quantitative structure-activity relationship (QSAR) study by multiple regression analysis. The best correlation between the observed and QSAR theoretical (Kd predicted) data was displayed at 2.5 ns. This study provides evidence that HSA binding sites I and II interact specifically with a variety of compounds through conformational adjustments of the protein structure in conjunction with ligand conformational adaptation to these sites. These results serve to explain the high ligand-promiscuity of HSA. © 2009 Wiley Periodicals, Inc. Biopolymers 93: 161–170, 2010.
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