title: Insights into the structural function of the complex of HIV-1 protease with TMC-126: molecular dynamics simulations and free-energy calculations.
abstract: The binding properties of the protein-inhibitor complex of human immunodeficiency virus type 1 (HIV-1) protease with the inhibitor TMC-126 are investigated by combining computational alanine scanning (CAS) mutagenesis with binding free-energy decomposition (BFED). The calculated results demonstrate that the flap region (residues 38-58) and the active site region (residues 23-32) in HIV-1 protease contribute 63.72% of the protease to the binding of the inhibitor. In particular, the mechanisms for the interactions of key residues of these species are fully explored and analyzed. Interestingly, the regression analyses show that both CAS and BFED based on the generalized Born model yield similar results, with a correlation coefficient of 0.94. However, compared to CAS, BFED is faster and can decompose the per-residue binding free-energy contributions into backbone and side-chain contributions. The results obtained in this study are useful for studying the binding mechanism between receptor and ligand and for designing potent inhibitors that can combat diseases.
authors.affiliation: National Synchrotron Radiation Laboratory, University of Science and Technology of China, Hefei, People's Republic of China.
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.forename: Ju-Guang
authors.initials: JG
authors.lastname: Han
authors.forename: Hang
authors.initials: H
authors.lastname: Chen
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.forename: Run-Ning
authors.initials: RN
authors.lastname: Zhao
authors.forename: Guang
authors.initials: G
authors.lastname: Liu
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Duan
mesh_terms: D000409:Alanine / Q000737:chemistry; D020134:Catalytic Domain; D016333:HIV Protease / Q000737:chemistry*; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D015497:HIV-1 / Q000737:chemistry* / Q000201:enzymology; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D013449:Sulfonamides / Q000737:chemistry*; D013816:Thermodynamics; D014520:Urethane / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: D017320:HIV Protease Inhibitors; D013449:Sulfonamides; C446340:UIC-94003; D014520:Urethane; D016333:HIV Protease; D000409:Alanine