title: pH-REMD simulations indicate that the catalytic aspartates of HIV-1 protease exist primarily in a monoprotonated state.
abstract: The protonation state of the catalytic aspartates of HIV-1 protease (HIVPR) is atypical and as a result is the subject of much debate. Modeling of the correct protonation state of the aspartates is vital in computational drug design. Using pH replica-exchange molecular dynamics, we simulated the apo and bound forms of HIV-1 protease with 12 different protease inhibitors to investigate the pKa of not only the catalytic dyad but also the other titrating residues in HIVPR. The results obtained from these simulations are compared to experiment where possible. This study provides evidence that the catalytic aspartates are primarily in a monoprotonated state for both the apo and bound forms of HIVPR in the pH range where generally most experiments and computational simulations occur.
authors.affiliation: Department of Chemistry, Quantum Theory Project, University of Florida , Gainesville, Florida 32611, United States.
authors.forename: T Dwight
authors.initials: TD
authors.lastname: McGee
authors.forename: Jesse
authors.initials: J
authors.lastname: Edwards
authors.forename: Adrian E
authors.initials: AE
authors.lastname: Roitberg
mesh_terms: D001224:Aspartic Acid / Q000737:chemistry*; D055162:Biocatalysis; D020134:Catalytic Domain; D015195:Drug Design; D016333:HIV Protease / Q000737:chemistry*; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D011522:Protons; D013816:Thermodynamics
chemical_list: D017320:HIV Protease Inhibitors; D011522:Protons; D001224:Aspartic Acid; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1