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Enumerating Pathways of Proton Abstraction Based on a Spatial and Electrostatic Analysis of Residues in the Catalytic Site

Public Library of Science
Publication Date
DOI: 10.1371/journal.pone.0039577
  • Research Article
  • Biology
  • Biochemistry
  • Enzymes
  • Enzyme Structure
  • Proteins
  • Protein Chemistry
  • Protein Structure
  • Biochemistry Simulations
  • Biophysics
  • Biophysics Simulations
  • Computational Biology
  • Biophysic Al Simulations
  • Chemistry
  • Chemical Reactions
  • Ionization
  • Computational Chemistry
  • Molecular Mechanics
  • Physical Chemistry
  • Ion Exchange
  • Computer Science
  • Algorithms
  • Computerized Simulations
  • Software Engineering
  • Software Tools
  • Physics
  • Biology
  • Computer Science
  • Physics


The pathways of proton abstraction (PA), a key aspect of most catalytic reactions, is often controversial and highly debated. Ultrahigh-resolution diffraction studies, molecular dynamics, quantum mechanics and molecular mechanic simulations are often adopted to gain insights in the PA mechanisms in enzymes. These methods require expertise and effort to setup and can be computationally intensive. We present a push button methodology – Proton abstraction Simulation (PRISM) – to enumerate the possible pathways of PA in a protein with known 3D structure based on the spatial and electrostatic properties of residues in the proximity of a given nucleophilic residue. Proton movements are evaluated in the vicinity of this nucleophilic residue based on distances, potential differences, spatial channels and characteristics of the individual residues (polarity, acidic, basic, etc). Modulating these parameters eliminates their empirical nature and also might reveal pathways that originate from conformational changes. We have validated our method using serine proteases and concurred with the dichotomy in PA in Class A β-lactamases, both of which are hydrolases. The PA mechanism in a transferase has also been corroborated. The source code is made available at

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