Hydrolysis of chemically distinct sites of human serum albumin by polyoxometalate: A hybrid QM/MM (ONIOM) study |
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| Authors: | Vindi M. Jayasinghe-Arachchige Qiaoyu Hu Gaurav Sharma Thomas J. Paul Marcus Lundberg David Quinonero Tatjana N. Parac-Vogt Rajeev Prabhakar |
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| Affiliation: | 1. Department of Chemistry, University of Miami, Coral Gables, Florida 33146;2. Department of Chemistry - Ångström Laboratory, Uppsala University, 751 21, Uppsala, Sweden;3. Department of Chemistry, Universitat de les Illes Balears, Palma de Mallorca, Spain;4. Department of Chemistry, KU Leuven, 3001, Leuven, Belgium |
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| Abstract: | 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. |
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| Keywords: | polyoxometalates human serum albumin peptide hydrolysis reaction mechanism QM/MM (ONIOM) method |
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