Understanding the enzyme-ligand complex: insights from all-atom simulations of butyrylcholinesterase inhibition.

All-atom molecular dynamics simulations of butyrylcholinesterase (BChE) sans inhibitor and in complex with each of 15 dialkyl phenyl phosphate derivatives were conducted to characterize inhibitor binding modes and strengths. Each system was sampled on the 250 ns timescale in explicit ionic solvent, for a total of over 4 μs of simulation time. A K-means algorithm was used to cluster the resulting structures into distinct binding modes, which were further characterized based on atomic-level contacts between inhibitor chemical groups and active site residues. Comparison of experimentally observed inhibition constants (KI) with the resulting contact tables provides structural explanations for relative binding coefficients and highlights several notable interaction motifs. These include ubiquitous contact between glycines in the oxyanion hole and the inhibitor phosphate group; a sterically driven binding preference for positional isomers that extend aromaticity; a stereochemical binding preference for choline-containing inhibitors, which mimic natural BChE substrates; and the mechanically induced opening of the omega loop region to fully expose the active site gorge in the presence of choline-containing inhibitors. Taken together, these observations can greatly inform future design of BChE inhibitors, and the approach reported herein is generalizable to other enzyme-inhibitor systems and similar complexes that depend on non-covalent molecular recognition.Communicated by Ramaswamy H. Sarma.