title: Ligand-receptor affinities computed by an adapted linear interaction model for continuum electrostatics and by protein conformational averaging.
abstract: Accurate calculations of free energies involved in small-molecule binding to a receptor are challenging. Interactions between ligand, receptor, and solvent molecules have to be described precisely, and a large number of conformational microstates has to be sampled, particularly for ligand binding to a flexible protein. Linear interaction energy models are computationally efficient methods that have found considerable success in the prediction of binding free energies. Here, we parametrize a linear interaction model for implicit solvation with coefficients adapted by ligand and binding site relative polarities in order to predict ligand binding free energies. Results obtained for a diverse series of ligands suggest that the model has good predictive power and transferability. We also apply implicit ligand theory and propose approximations to average contributions of multiple ligand-receptor poses built from a protein conformational ensemble and find that exponential averages require proper energy discrimination between plausible binding poses and false-positives (i.e., decoys). The linear interaction model and the averaging procedures presented can be applied independently of each other and of the method used to obtain the receptor structural representation.
authors: Department of Biochemistry, Instituto de Química, Universidade de São Paulo , Av. Prof. Lineu Prestes 748, 05508-900, São Paulo, SP, Brazil.
authors: Ariane
authors: A
authors: Nunes-Alves
authors: Guilherme Menegon
authors: GM
authors: Arantes
mesh_terms: D017122:Bacteriophage T4 / Q000737:chemistry / Q000201:enzymology; D001665:Binding Sites; D054303:HIV Reverse Transcriptase / Q000737:chemistry*; D015497:HIV-1 / Q000737:chemistry / Q000201:enzymology; D006801:Humans; D008024:Ligands; D016014:Linear Models; D056004:Molecular Dynamics Simulation / Q000706:statistics & numerical data*; D009113:Muramidase / Q000737:chemistry*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D055672:Static Electricity; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D008024:Ligands; D058570:TOR Serine-Threonine Kinases; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D009113:Muramidase