Computational characterization of how the VX nerve agent binds human serum paraoxonase 1

Steven Z. Fairchild, Matthew W. Peterson, Adel Hamza, Chang Guo Zhan, Douglas M. Cerasoli, Wenling E. Chang

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


Human serum paraoxonase 1 (HuPON1) is an enzyme that can hydrolyze various chemical warfare nerve agents including VX. A previous study has suggested that increasing HuPON1's VX hydrolysis activity one to two orders of magnitude would make the enzyme an effective countermeasure for in vivo use against VX. This study helps facilitate further engineering of HuPON1 for enhanced VX-hydrolase activity by computationally characterizing HuPON1's tertiary structure and how HuPON1 binds VX. HuPON1's structure is first predicted through two homology modeling procedures. Docking is then performed using four separate methods, and the stability of each bound conformation is analyzed through molecular dynamics and solvated interaction energy calculations. The results show that VX's lone oxygen atom has a strong preference for forming a direct electrostatic interaction with HuPON1's active site calcium ion. Various HuPON1 residues are also detected that are in close proximity to VX and are therefore potential targets for future mutagenesis studies. These include E53, H115, N168, F222, N224, L240, D269, I291, F292, and V346. Additionally, D183 was found to have a predicted pKa near physiological pH. Given D183's location in HuPON1's active site, this residue could potentially act as a proton donor or accepter during hydrolysis. The results from the binding simulations also indicate that steered molecular dynamics can potentially be used to obtain accurate binding predictions even when starting with a closed conformation of a protein's binding or active site.

Original languageEnglish
Pages (from-to)97-109
Number of pages13
JournalJournal of Molecular Modeling
Issue number1
StatePublished - Jan 2011

Bibliographical note

Funding Information:
This research was supported by the Defense Threat Reduction Agency-Joint Science and Technology Office, Medical S&T Division. The opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the U.S. Army or the Department of Defense.


  • Binding
  • Homology model
  • HuPON1
  • Solvated interaction energy
  • Steered molecular dynamics
  • VX

ASJC Scopus subject areas

  • Catalysis
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Computational Theory and Mathematics
  • Inorganic Chemistry


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