title: Complexity in modeling and understanding protonation states: computational titration of HIV-1-protease-inhibitor complexes.
abstract: The computational-titration (CT) algorithm based on the 'natural' Hydropathic INTeractions (HINT) force field is described. The HINT software model is an empirical, non-Newtonian force field derived from experimentally measured partition coefficients for solvent transfer between octanol and H(2)O (log P(o/w)). The CT algorithm allows the identification, modeling, and optimization of multiple protonation states of residues and ligand functional groups at the protein-ligand active site. The importance of taking into account pH and ionization states of residues, which strongly affect the process of ligand binding, for correctly predicting binding free energies is discussed. The application of the CT protocol to a set of six cyclic inhibitors in their complexes with HIV-1 protease is presented, and the advance of HINT as a virtual-screening tool is outlined.
authors.affiliation: Department of Medicinal Chemistry & Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, VA 23298-0540, USA.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Tripathi
authors.forename: Micaela
authors.initials: M
authors.lastname: Fornabaio
authors.forename: Francesca
authors.initials: F
authors.lastname: Spyrakis
authors.forename: Andrea
authors.initials: A
authors.lastname: Mozzarelli
authors.forename: Pietro
authors.initials: P
authors.lastname: Cozzini
authors.forename: Glen E
authors.initials: GE
authors.lastname: Kellogg
mesh_terms: D019295:Computational Biology / Q000379:methods*; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism; D008956:Models, Chemical; D011485:Protein Binding / Q000502:physiology; D011522:Protons; D017186:Titrimetry / Q000379:methods
chemical_list: D017320:HIV Protease Inhibitors; D011522:Protons