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

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish (US)
JournalJournal of Computational Chemistry
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Serum Albumin
Hydrolysis
Distinct
Water
Dipeptides
Attack
Peptides
Internal
polyoxometalate I
Human
Limiting
Line
Range of data

Keywords

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

ASJC Scopus subject areas

  • Chemistry(all)
  • Computational Mathematics

Cite this

Hydrolysis of chemically distinct sites of human serum albumin by polyoxometalate : A hybrid QM/MM (ONIOM) study. / Jayasinghe-Arachchige, Vindi M.; Hu, Qiaoyu; Sharma, Gaurav; Paul, Thomas J.; Lundberg, Marcus; Quinonero, David; Parac-Vogt, Tatjana N.; Prabhakar, Rajeev.

In: Journal of Computational Chemistry, 01.01.2018.

Research output: Contribution to journalArticle

Jayasinghe-Arachchige, Vindi M. ; Hu, Qiaoyu ; Sharma, Gaurav ; Paul, Thomas J. ; Lundberg, Marcus ; Quinonero, David ; Parac-Vogt, Tatjana N. ; Prabhakar, Rajeev. / Hydrolysis of chemically distinct sites of human serum albumin by polyoxometalate : A hybrid QM/MM (ONIOM) study. In: Journal of Computational Chemistry. 2018.
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