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

ABSTRACT: 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 ?s 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.

SUBMITTER: Alvarado W

PROVIDER: S-EPMC6851450 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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

Alvarado Walter W Bremer Parker Ladd PL Choy Angela A Dinh Helen N HN Eung Aingty A Gonzalez Jeannette J Ly Phillippe P Tran Trina T Nakayama Kensaku K Schwans Jason P JP Sorin Eric J EJ

Journal of biomolecular structure & dynamics 20190407 4

All-atom molecular dynamics simulations of butyrylcholinesterase (BChE) <i>sans</i> 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 ...[more]

PMID: 30909811

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Project description:The process of protein complex dissociation remains to be understood at the atomic level of detail. Computers now allow microsecond timescale molecular-dynamics simulations, which make the visualization of such processes possible. Here, we investigated the dissociation process of the EphA2-SHIP2 SAM-SAM domain heterodimer complex using unrestrained all-atom molecular-dynamics simulations. Previous studies on this system have shown that alternate configurations are sampled, that their interconversion can be fast, and that the complex is dynamic by nature. Starting from different NMR-derived structures, mutants were designed to stabilize a subset of configurations by swapping ion pairs across the protein-protein interface. We focused on two mutants, K956D/D1235K and R957D/D1223R, with attenuated binding affinity compared with the wild-type proteins. In contrast to calculations on the wild-type complexes, the majority of simulations of these mutants showed protein dissociation within 2.4 ?s. During the separation process, we observed domain rotation and pivoting as well as a translation and simultaneous rolling, typically to alternate and weaker binding interfaces. Several unsuccessful recapturing attempts occurred once the domains were moderately separated. An analysis of protein solvation suggests that the dissociation process correlates with a progressive loss of protein-protein contacts. Furthermore, an evaluation of internal protein dynamics using quasi-harmonic and order parameter analyses indicates that changes in protein internal motions are expected to contribute significantly to the thermodynamics of protein dissociation. Considering protein association as the reverse of the separation process, the initial role of charged/polar interactions is emphasized, followed by changes in protein and solvent dynamics. The trajectories show that protein separation does not follow a single distinct pathway, but suggest that the mechanism of dissociation is common in that it initially involves transitions to surfaces with fewer, less favorable contacts compared with those seen in the fully formed complex.

Dataset Information

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

Publications

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

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