title: New parameterization approaches of the LIE method to improve free energy calculations of PlmII-Inhibitors complexes.
abstract: The standard parameterization of the Linear Interaction Energy (LIE) method has been applied with quite good results to reproduce the experimental absolute binding free energies for several protein-ligand systems. However, we found that this parameterization failed to reproduce the experimental binding free energy of Plasmepsin II (PlmII) in complexes with inhibitors belonging to four dissimilar scaffolds. To overcome this fact, we developed three approaches of LIE, which combine systematic approaches to predict the inhibitor-specific values of α, β, and γ parameters, to gauge their ability to calculate the absolute binding free energies for these PlmII-Inhibitor complexes. Specifically: (i) we modified the linear relationship between the weighted nonpolar desolvation ratio (WNDR) and the α parameter, by introducing two models of the β parameter determined by the free energy perturbation (FEP) method in the absence of the constant term γ, and (ii) we developed a new parameterization model to investigate the linear correlation between WNDR and the correction term γ. Using these parameterizations, we were able to reproduce the experimental binding free energy from these systems with mean absolute errors lower than 1.5 kcal/mol.
authors.affiliation: Laboratorio de Biología Computacional y Diseño de Proteínas, Centro de Estudios de Proteínas, Facultad de Biología, Universidad de La Habana, Cuba. pascutti@biof.ufrj.br
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Valiente
authors.forename: Alejandro
authors.initials: A
authors.lastname: Gil
authors.forename: Paulo R
authors.initials: PR
authors.lastname: Batista
authors.forename: Ernesto R
authors.initials: ER
authors.lastname: Caffarena
authors.forename: Tirso
authors.initials: T
authors.lastname: Pons
authors.forename: Pedro G
authors.initials: PG
authors.lastname: Pascutti
mesh_terms: D000465:Algorithms; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D057055:Aspartic Acid Proteases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D056004:Molecular Dynamics Simulation; D018583:Pliability; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D000962:Antimalarials; D004791:Enzyme Inhibitors; D008024:Ligands; D015800:Protozoan Proteins; D057055:Aspartic Acid Proteases; D016282:Aspartic Acid Endopeptidases; C100637:plasmepsin II