Conformational energy landscape of the acyl pocket loop in acetylcholinesterase: a Monte Carlo-generalized Born model study
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Updated: Aug 22, 2026

Modeling Ligands into Maps Derived from Electron Cryomicroscopy
Published on: July 19, 2024
Louis Carlacci1, Charles B Millard, Mark A Olson
1Army High Performance Computing Research Center, Network Computing Services, Inc., 1425 Porter Street, Frederick, MD 21702, USA.
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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