Open AccessEnergetics of Ortho-7 (Oxime Drug) Translocation through the Active-Site Gorge of Tabun Conjugated Acetylcholinesterase
Author(s) -
Vivek Sinha,
Bishwajit Ganguly,
Tusar Bandyopadhyay
Publication year - 2012
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0040188
Subject(s) - tabun , oxime , chemistry , acetylcholinesterase , active site , energetics , molecular dynamics , biophysics , binding site , stereochemistry , computational chemistry , enzyme , nerve agent , biochemistry , biology , ecology
Oxime drugs translocate through the 20 Å active-site gorge of acetylcholinesterase in order to liberate the enzyme from organophosphorus compounds’ (such as tabun) conjugation. Here we report bidirectional steered molecular dynamics simulations of oxime drug (Ortho-7) translocation through the gorge of tabun intoxicated enzyme, in which time dependent external forces accelerate the translocation event. The simulations reveal the participation of drug-enzyme hydrogen bonding, hydrophobic interactions and water bridges between them. Employing nonequilibrium theorems that recovers the free energy from irreversible work done, we reconstruct potential of mean force along the translocation pathway such that the desired quantity represents an unperturbed system. The potential locates the binding sites and barriers for the drug to translocate inside the gorge. Configurational entropic contribution of the protein-drug binding entity and the role of solvent translational mobility in the binding energetics is further assessed.