Computational conformational analysis of α-thrombin inhibitors possessing distinct scaffolds in aqueous solution and...

Recent computational simulations on protein-ligand binding/unbinding have precisely been uncovering the ligand-binding process at the atomic level. In the process, the non-specific binding of ligands to the target site is suggested to occur before binding to the target. We in this study analyzed the conformations of ligands under the non-specific binding on a protein surface to figure out the differences in the conformational characteristics in aqueous solution using the 55-ns molecular dynamic simulation. As for the protein surface, we constructed an artificial β-sheet, composed of poly-alanine residues (Ala-sheet). For the ligands, the four α-thrombin inhibitors possessing two scaffolds with distinct hydrophobicity profiles were used. During the simulation, all the inhibitors kept interaction with Ala-sheet and had the limited conformational fluctuations compared with in aqueous solution. The representative conformations obtained from the cluster analysis showed that two of hydrophobic inhibitors adopted the extended conformations in aqueous solution and also on Ala-sheet. For the other two hydrophilic inhibitors, the conformations in aqueous solution adopted the bent conformation with two terminal hydrophobic rings closely packed. On Ala-sheet, contrarily, the two hydrophobic rings were open and took the extended conformations, which were placed on the sheet as a foothold. The charged moieties in the hydrophilic inhibitors were protruded into aqueous environment with the extended conformation. The conformational characteristics of the inhibitors in aqueous solution and Ala-sheet varied likely by chemical features or structures of the inhibitors, but each was considered to be physicochemically reasonable.