Conformational energy landscape of the acyl pocket loop in acetylcholinesterase: a Monte Carlo-generalized Born model study

Biophysical Chemistry
Louis CarlacciMark A Olson

Abstract

The X-ray crystal structure of the reaction product of acetylcholinesterase (AChE) with the inhibitor diisopropylphosphorofluoridate (DFP) showed significant structural displacement in a loop segment of residues 287-290. To understand this conformational selection, a Monte Carlo (MC) simulation study was performed of the energy landscape for the loop segment. A computational strategy was applied by using a combined simulated annealing and room temperature Metropolis sampling approach with solvent polarization modeled by a generalized Born (GB) approximation. Results from thermal annealing reveal a landscape topology of broader basin opening and greater distribution of energies for the displaced loop conformation, while the ensemble average of conformations at 298 K favored a shift in populations toward the native by a free-energy difference in good agreement with the estimated experimental value. Residue motions along a reaction profile of loop conformational reorganization are proposed where Arg-289 is critical in determining electrostatic effects of solvent interaction versus Coulombic charging.

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Citations

Jan 27, 2009·Journal of Chemical Information and Modeling·Guo LiYan Zhang
May 14, 2009·The Journal of Physical Chemistry. B·Mihail Mihailescu, Hagai Meirovitch
Mar 10, 2017·Molecular Diversity·Bing NiuYuhui Zhang
May 1, 2021·Biomolecules·Danna De BoerEric J Sorin

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