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Ligand-Binding-Site Structure Refinement Using Molecular Dynamics with Restraints Derived from Predicted Binding Site Templates.

ABSTRACT: Accurate modeling of ligand-binding-site structures plays a critical role in structure-based virtual screening. However, the structures of the ligand-binding site in most predicted protein models are generally of low quality and need refinements. In this work, we present a ligand-binding-site structure refinement protocol using molecular dynamics simulation with restraints derived from predicted binding site templates. Our benchmark validation shows great performance for 40 diverse sets of proteins from the Astex list. The ligand-binding sites on modeled protein structures are consistently refined using our method with an average C? RMSD improvement of 0.90 Å. Comparison of ligand binding modes from ligand docking to initial unrefined and refined structures shows an average of 1.97 Å RMSD improvement in the refined structures. These results demonstrate a promising new method of structure refinement for protein ligand-binding-site structures.

SUBMITTER: Guterres H

PROVIDER: S-EPMC6884403 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Ligand-Binding-Site Structure Refinement Using Molecular Dynamics with Restraints Derived from Predicted Binding Site Templates.

Guterres Hugo H Lee Hui Sun HS Im Wonpil W

Journal of chemical theory and computation 20191014 11

Accurate modeling of ligand-binding-site structures plays a critical role in structure-based virtual screening. However, the structures of the ligand-binding site in most predicted protein models are generally of low quality and need refinements. In this work, we present a ligand-binding-site structure refinement protocol using molecular dynamics simulation with restraints derived from predicted binding site templates. Our benchmark validation shows great performance for 40 diverse sets of prote ...[more]

PMID: 31557013

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Project description:Exhaustive exploration of molecular interactions at the level of complete proteomes requires efficient and reliable computational approaches to protein function inference. Ligand docking and ranking techniques show considerable promise in their ability to quantify the interactions between proteins and small molecules. Despite the advances in the development of docking approaches and scoring functions, the genome-wide application of many ligand docking/screening algorithms is limited by the quality of the binding sites in theoretical receptor models constructed by protein structure prediction. In this study, we describe a new template-based method for the local refinement of ligand-binding regions in protein models using remotely related templates identified by threading. We designed a Support Vector Regression (SVR) model that selects correct binding site geometries in a large ensemble of multiple receptor conformations. The SVR model employs several scoring functions that impose geometrical restraints on the C? positions, account for the specific chemical environment within a binding site and optimize the interactions with putative ligands. The SVR score is well correlated with the RMSD from the native structure; in 47% (70%) of the cases, the Pearson's correlation coefficient is >0.5 (>0.3). When applied to weakly homologous models, the average heavy atom, local RMSD from the native structure of the top-ranked (best of top five) binding site geometries is 3.1Å (2.9Å) for roughly half of the targets; this represents a 0.1 (0.3)Å average improvement over the original predicted structure. Focusing on the subset of strongly conserved residues, the average heavy atom RMSD is 2.6Å (2.3Å). Furthermore, we estimate the upper bound of template-based binding site refinement using only weakly related proteins to be ?2.6Å RMSD. This value also corresponds to the plasticity of the ligand-binding regions in distant homologues. The Binding Site Refinement (BSR) approach is available to the scientific community as a web server that can be accessed at http://cssb.biology.gatech.edu/bsr/.

Dataset Information

Ligand-Binding-Site Structure Refinement Using Molecular Dynamics with Restraints Derived from Predicted Binding Site Templates.

Publications

Ligand-Binding-Site Structure Refinement Using Molecular Dynamics with Restraints Derived from Predicted Binding Site Templates.

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