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The FTMap family of web servers for determining and characterizing ligand-binding hot spots of proteins.

ABSTRACT: FTMap is a computational mapping server that identifies binding hot spots of macromolecules-i.e., regions of the surface with major contributions to the ligand-binding free energy. To use FTMap, users submit a protein, DNA or RNA structure in PDB (Protein Data Bank) format. FTMap samples billions of positions of small organic molecules used as probes, and it scores the probe poses using a detailed energy expression. Regions that bind clusters of multiple probe types identify the binding hot spots in good agreement with experimental data. FTMap serves as the basis for other servers, namely FTSite, which is used to predict ligand-binding sites, FTFlex, which is used to account for side chain flexibility, FTMap/param, used to parameterize additional probes and FTDyn, for mapping ensembles of protein structures. Applications include determining the druggability of proteins, identifying ligand moieties that are most important for binding, finding the most bound-like conformation in ensembles of unliganded protein structures and providing input for fragment-based drug design. FTMap is more accurate than classical mapping methods such as GRID and MCSS, and it is much faster than the more-recent approaches to protein mapping based on mixed molecular dynamics. By using 16 probe molecules, the FTMap server finds the hot spots of an average-size protein in <1 h. As FTFlex performs mapping for all low-energy conformers of side chains in the binding site, its completion time is proportionately longer.

SUBMITTER: Kozakov D

PROVIDER: S-EPMC4762777 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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The FTMap family of web servers for determining and characterizing ligand-binding hot spots of proteins.

Kozakov Dima D Grove Laurie E LE Hall David R DR Bohnuud Tanggis T Mottarella Scott E SE Luo Lingqi L Xia Bing B Beglov Dmitri D Vajda Sandor S

Nature protocols 20150409 5

FTMap is a computational mapping server that identifies binding hot spots of macromolecules-i.e., regions of the surface with major contributions to the ligand-binding free energy. To use FTMap, users submit a protein, DNA or RNA structure in PDB (Protein Data Bank) format. FTMap samples billions of positions of small organic molecules used as probes, and it scores the probe poses using a detailed energy expression. Regions that bind clusters of multiple probe types identify the binding hot spot ...[more]

PMID: 25855957

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Project description:NMR spectroscopy and molecular dynamics (MD) simulations were used to probe the structure and dynamics of complexes of three phosphotyrosine-derived peptides with the Src SH2 domain in an effort to uncover a structural explanation for enthalpy-entropy compensation observed in the binding thermodynamics. The series of phosphotyrosine peptide derivatives comprises the natural pYEEI Src SH2 ligand, a constrained mimic, in which the phosphotyrosine (pY) residue is preorganized in the bound conformation for the purpose of gaining an entropic advantage to binding, and a flexible analogue of the constrained mimic. The expected gain in binding entropy of the constrained mimic was realized; however, a balancing loss in binding enthalpy was also observed that could not be rationalized from the crystallographic structures. We examined protein dynamics to evaluate whether the observed enthalpic penalty might be the result of effects arising from altered motions in the complex. (15)N-relaxation studies and positional fluctuations from molecular dynamics indicate that the main-chain dynamics of the protein show little variation among the three complexes. Root mean squared (rms) coordinate deviations vary by less than 1.5 A for all non-hydrogen atoms for the crystal structures and in the ensemble average structures calculated from the simulations. In contrast to this striking similarity in the structures and dynamics, there are a number of large chemical shift differences from residues across the binding interface, but particularly from key Src SH2 residues that interact with pY, the "hot spot" residue, which contributes about one-half of the binding free energy. Rank-order correlations between chemical shifts and ligand binding enthalpy for several pY-binding residues, coupled with available mutagenesis and calorimetric data, suggest that subtle structural perturbations (<1 A) from the conformational constraint of the pY residue sufficiently alter the geometry of enthalpically critical interactions in the binding pocket to cause the loss of binding enthalpy, leading to the observed enthalpy-entropy compensation. We find no evidence to support the premise that enthalpy-entropy compensation is an inherent property and conclude that preorganization of Src SH2 ligand residues involved in binding hot spots may eventuate in suboptimal interactions with the domain. We propose that introducing constraints elsewhere in the ligand could minimize enthalpy-entropy compensation effects. The results illustrate the utility of the NMR chemical shift to highlight small, but energetically significant, perturbations in structure that might otherwise go unnoticed in an apparently rigid protein.

Dataset Information

The FTMap family of web servers for determining and characterizing ligand-binding hot spots of proteins.

Publications

The FTMap family of web servers for determining and characterizing ligand-binding hot spots of proteins.

Similar Datasets

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