Hydrolysis of chemically distinct sites of human serum albumin by polyoxometalate: A hybrid QM/MM (ONIOM) study

In this study, mechanisms of hydrolysis of all four chemically diverse cleavage sites of human serum albumin (HSA) by [Zr(OH)(PW11O39)]4− (ZrK) have been investigated using the hybrid two‐layer QM/MM (ONIOM) method. These reactions have been proposed to occur through the following two mechanisms: internal attack (IA) and water assisted (WA). In both mechanisms, the cleavage of the peptide bond in the Cys392‐Glu393 site of HSA is predicted to occur in the rate‐limiting step of the mechanism. With the barrier of 27.5 kcal/mol for the hydrolysis of this site, the IA mechanism is found to be energetically more favorable than the WA mechanism (barrier = 31.6 kcal/mol). The energetics for the IA mechanism are in line with the experimentally measured values for the cleavage of a wide range of dipeptides. These calculations also suggest an energetic preference (Cys392‐Glu393, Ala257‐Asp258, Lys313‐Asp314, and Arg114‐Leu115) for the hydrolysis of all four sites of HSA. © 2018 Wiley Periodicals, Inc. Mechanisms for the hydrolysis of all four chemically distinct cleavage sites of human serum albumin (HSA) catalyzed by a Zr‐containing polyoxometalate [Zr(OH)(PW11O39)]4−. They are proposed using the hybrid two‐layer QM/MM (ONIOM) calculations.