title: Contribution of conformer focusing to the uncertainty in predicting free energies for protein-ligand binding.
abstract: When a ligand binds to a protein, it is typically not in the lowest-energy conformation for the unbound ligand and there is also a loss of conformational degrees of freedom. The free-energy change for this "conformer focusing" is addressed here formally, and the associated errors with its estimation or neglect are considered in the context of scoring functions for protein-ligand docking and computation of absolute free energies of binding. Specific applications for inhibition of HIV-1 reverse transcriptase are reported. It is concluded that the uncertainties from this source alone are sufficient to preclude the viability of current docking methodology for rank-ordering of diverse compounds in high-throughput virtual screening.
authors.affiliation: Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, USA.
authors.forename: Julian
authors.initials: J
authors.lastname: Tirado-Rives
authors.forename: William L
authors.initials: WL
authors.lastname: Jorgensen
mesh_terms: D001665:Binding Sites; D015195:Drug Design; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D008024:Ligands; D011506:Proteins