title: Conformational energy landscape of the acyl pocket loop in acetylcholinesterase: a Monte Carlo-generalized Born model study.
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.
authors.affiliation: Army High Performance Computing Research Center, Network Computing Services, Inc., 1425 Porter Street, Frederick, MD 21702, USA.
authors.forename: Louis
authors.initials: L
authors.lastname: Carlacci
authors.forename: Charles B
authors.initials: CB
authors.lastname: Millard
authors.forename: Mark A
authors.initials: MA
authors.lastname: Olson
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D000215:Acylation; D000818:Animals; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004735:Energy Transfer; D007531:Isoflurophate / Q000378:metabolism*; D008958:Models, Molecular; D009010:Monte Carlo Method; D011487:Protein Conformation; D013816:Thermodynamics; D014101:Torpedo / Q000378:metabolism*
chemical_list: D007531:Isoflurophate; D000110:Acetylcholinesterase