Empirical Valence Bond Simulations of Organophosphate Hydrolysis: Theory and Practice

Methods Enzymol. 2018:607:3-51. doi: 10.1016/bs.mie.2018.06.007. Epub 2018 Aug 16.

Abstract

Recent years have seen an explosion of interest in understanding the mechanisms of phosphate ester hydrolysis in biological systems, using a range of computational approaches, each with different advantages and limitations. In this contribution, we present the empirical valence bond (EVB) approach as a powerful tool for modeling biochemical reactivity, using the example of organophosphate hydrolysis by diisopropyl fluorophosphatase as our model reaction. We walk the reader through the protocol for setting up and performing EVB simulations, as well as key technical considerations that need to be taken into account. Finally, we provide examples of the applications of the EVB approach to understanding different experimental observables.

Keywords: Computational enzymology; Diisopropyl fluorophosphatase; Empirical valence bond; Enzyme mechanisms; Organophosphate hydrolysis.

MeSH terms

  • Computer Simulation
  • Cryoelectron Microscopy / instrumentation
  • Cryoelectron Microscopy / methods
  • Crystallography, X-Ray / instrumentation
  • Hydrolysis
  • Models, Molecular*
  • Nuclear Magnetic Resonance, Biomolecular / instrumentation
  • Nuclear Magnetic Resonance, Biomolecular / methods
  • Organophosphates / metabolism*
  • Phosphoric Triester Hydrolases / chemistry
  • Phosphoric Triester Hydrolases / metabolism*
  • Phosphoric Triester Hydrolases / ultrastructure
  • Protein Structure, Tertiary
  • Thermodynamics

Substances

  • Organophosphates
  • Phosphoric Triester Hydrolases