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Recognizing protein-ligand binding sites by global structural alignment and local geometry refinement.

ABSTRACT: Proteins perform functions through interacting with other molecules. However, structural details for most of the protein-ligand interactions are unknown. We present a comparative approach (COFACTOR) to recognize functional sites of protein-ligand interactions using low-resolution protein structural models, based on a global-to-local sequence and structural comparison algorithm. COFACTOR was tested on 501 proteins, which harbor 582 natural and drug-like ligand molecules. Starting from I-TASSER structure predictions, the method successfully identifies ligand-binding pocket locations for 65% of apo receptors with an average distance error 2 Å. The average precision of binding-residue assignments is 46% and 137% higher than that by FINDSITE and ConCavity. In CASP9, COFACTOR achieved a binding-site prediction precision 72% and Matthews correlation coefficient 0.69 for 31 blind test proteins, which was significantly higher than all other participating methods. These data demonstrate the power of structure-based approaches to protein-ligand interaction predictions applicable for genome-wide structural and functional annotations.

SUBMITTER: Roy A

PROVIDER: S-EPMC3372652 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Recognizing protein-ligand binding sites by global structural alignment and local geometry refinement.

Roy Ambrish A Zhang Yang Y

Structure (London, England : 1993) 20120503 6

Proteins perform functions through interacting with other molecules. However, structural details for most of the protein-ligand interactions are unknown. We present a comparative approach (COFACTOR) to recognize functional sites of protein-ligand interactions using low-resolution protein structural models, based on a global-to-local sequence and structural comparison algorithm. COFACTOR was tested on 501 proteins, which harbor 582 natural and drug-like ligand molecules. Starting from I-TASSER st ...[more]

PMID: 22560732

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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

Recognizing protein-ligand binding sites by global structural alignment and local geometry refinement.

Publications

Recognizing protein-ligand binding sites by global structural alignment and local geometry refinement.

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