title: Insights into the functional role of protonation states in the HIV-1 protease-BEA369 complex: molecular dynamics simulations and free energy calculations.
abstract: The molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method combined with molecular dynamics (MD) simulations were used to investigate the functional role of protonation in human immunodeficiency virus type 1 (HIV-1) protease complexed with the inhibitor BEA369. Our results demonstrate that protonation of two aspartic acids (Asp25/Asp25') has a strong influence on the dynamics behavior of the complex, the binding free energy of BEA369, and inhibitor-residue interactions. Relative binding free energies calculated using the MM-PBSA method show that protonation of Asp25 results in the strongest binding of BEA369 to HIV-1 protease. Inhibitor-residue interactions computed by the theory of free energy decomposition also indicate that protonation of Asp25 has the most favorable effect on binding of BEA369. In addition, hydrogen-bond analysis based on the trajectories of the MD simulations shows that protonation of Asp25 strongly influences the water-mediated link of a conserved water molecule, Wat301. We expect that the results of this study will contribute significantly to binding calculations for BEA369, and to the design of high affinity inhibitors.
authors.affiliation: Shandong Normal University, Jinan, China.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Chen
authors.forename: Maoyou
authors.initials: M
authors.lastname: Yang
authors.forename: Guodong
authors.initials: G
authors.lastname: Hu
authors.forename: Shuhua
authors.initials: S
authors.lastname: Shi
authors.forename: Changhong
authors.initials: C
authors.lastname: Yi
authors.forename: Qinggang
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D001224:Aspartic Acid / Q000737:chemistry; D016333:HIV Protease / Q000737:chemistry*; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D007189:Indans / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011522:Protons; D013400:Sugar Acids / Q000737:chemistry*; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
chemical_list: C545957:BEA 369; D017320:HIV Protease Inhibitors; D007189:Indans; D011522:Protons; D013400:Sugar Acids; D014867:Water; D001224:Aspartic Acid; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1