Dataset Information

Modeling Protein-Ligand Binding by Mining Minima.

ABSTRACT: We present the first application of the mining minima algorithm to protein-small molecule binding. This end-point approach use an empirical force field and implicit solvent models, treats the protein binding-site as fully flexible and estimates free energies as sums over local energy wells. The calculations are found to yield encouraging agreement with experiment for three sets of HIV-1protease inhibitors and a set of phosphodiesterase 10a inhibitors. The contributions of various aspects of the model to its accuracy are examined, and the Poisson-Boltzmann correction is found to be the most critical. Interestingly, the computed changes in configurational entropy upon binding fall roughly along the same entropy-energy correlation previously observed for smaller host-guest systems. Strengths and weaknesses of the method are discussed, as are the prospects for enhancing accuracy and speed.

SUBMITTER: Chen W

PROVIDER: S-EPMC3359898 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Publications

Modeling Protein-Ligand Binding by Mining Minima.

Chen Wei W Gilson Michael K MK Webb Simon P SP Potter Michael J MJ

Journal of chemical theory and computation 20101008 11

We present the first application of the mining minima algorithm to protein-small molecule binding. This end-point approach use an empirical force field and implicit solvent models, treats the protein binding-site as fully flexible and estimates free energies as sums over local energy wells. The calculations are found to yield encouraging agreement with experiment for three sets of HIV-1protease inhibitors and a set of phosphodiesterase 10a inhibitors. The contributions of various aspects of the ...[more]

PMID: 22639555

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Project description:BACKGROUND: Models that are capable of reliably predicting binding affinities for protein-ligand complexes play an important role the field of structure-guided drug design. METHODS: Here, we begin by applying the computational geometry technique of Delaunay tessellation to each set of atomic coordinates for over 1400 diverse macromolecular structures, for the purpose of deriving a four-body statistical potential that serves as a topological scoring function. Next, we identify a second, independent set of three hundred protein-ligand complexes, having both high-resolution structures and known dissociation constants. Two-thirds of these complexes are randomly selected to train a predictive model of binding affinity as follows: two tessellations are generated in each case, one for the entire complex and another strictly for the isolated protein without its bound ligand, and a topological score is computed for each tessellation with the four-body potential. Predicted protein-ligand binding affinity is then based on an empirically derived linear function of the difference between both topological scores, one that appropriately scales the value of this difference. RESULTS: A comparison between experimental and calculated binding affinity values over the two hundred complexes reveals a Pearson's correlation coefficient of r = 0.79 with a standard error of SE = 1.98 kcal/mol. To validate the method, we similarly generated two tessellations for each of the remaining protein-ligand complexes, computed their topological scores and the difference between the two scores for each complex, and applied the previously derived linear transformation of this topological score difference to predict binding affinities. For these one hundred complexes, we again observe a correlation of r = 0.79 (SE = 1.93 kcal/mol) between known and calculated binding affinities. Applying our model to an independent test set of high-resolution structures for three hundred diverse enzyme-inhibitor complexes, each with an experimentally known inhibition constant, also yields a correlation of r = 0.79 (SE = 2.39 kcal/mol) between experimental and calculated binding energies. CONCLUSIONS: Lastly, we generate predictions with our model on a diverse test set of one hundred protein-ligand complexes previously used to benchmark 15 related methods, and our correlation of r = 0.66 between the calculated and experimental binding energies for this dataset exceeds those of the other approaches. Compared with these related prediction methods, our approach stands out based on salient features that include the reliability of our model, combined with the rapidity of the generated predictions, which are less than one second for an average sized complex.

Dataset Information

Modeling Protein-Ligand Binding by Mining Minima.

Publications

Modeling Protein-Ligand Binding by Mining Minima.

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