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

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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7 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)51-61
Number of pages11
JournalJournal of Computational Chemistry
Issue number1
StatePublished - Jan 5 2019


  • QM/MM (ONIOM) method
  • human serum albumin
  • peptide hydrolysis
  • polyoxometalates
  • reaction mechanism

ASJC Scopus subject areas

  • Chemistry(all)
  • Computational Mathematics


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