ci9b00416_si_001.pdf (2.49 MB)
De Novo Prediction of Binders and Nonbinders for T4 Lysozyme by gREST Simulations
journal contribution
posted on 2019-08-21, 15:17 authored by Ai Niitsu, Suyong Re, Hiraku Oshima, Motoshi Kamiya, Yuji SugitaMolecular
recognition underpins all specific protein–ligand
interactions and is essential for biomolecular functions. The prediction
of canonical binding poses and distinguishing binders from nonbinders
are much sought after goals. Here, we apply the generalized replica
exchange with solute tempering method, gREST, combined with a flat-bottom
potential to evaluate binder and nonbinder interactions with a T4
lysozyme Leu99Ala mutant. The buried hydrophobic cavity and possibility
of coupled conformational changes in this protein make binding predictions
difficult. The present gREST simulations, enabling enhanced flexibilities
of the ligand and protein residues near the binding site, sample bindings
in multiple poses, and correct portrayal of X-ray structures. The
free-energy profiles of binders (benzene, ethylbenzene, and n-hexylbenzene) are distinct from those of nonbinders (phenol
and benzaldehyde). Bindings of the two larger molecules seem to be
associated with a structural change toward an excited conformation
of the protein, which agrees with experimental findings. The protocol
is generally applicable to various proteins having buried cavities
with limited access for ligands with different shapes, sizes, and
chemical properties.
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replica exchangenonbinder interactionsbinding predictionsT 4 LysozymeDe Novo Predictionprotein residuescavitychemical propertiesgREST simulationsbinding sitefree-energy profilesgREST Simulations Molecular recognitioncanonical bindingX-ray structuresligandbiomolecular functionsT 4 lysozyme Leu 99Alasample bindings
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