title: Effect of allosteric molecules on structure and drug affinity of HIV-1 protease by molecular dynamics simulations.
abstract: Recent experiments show that small molecules can bind onto the allosteric sites of HIV-1 protease (PR), which provides a starting point for developing allosteric inhibitors. However, the knowledge of the effect of such binding on the structural dynamics and binding free energy of the active site inhibitor and PR is still lacking. Here, we report 200ns long molecular dynamics simulation results to gain insight into the influences of two allosteric molecules (1H-indole-6-carboxylic acid, 1F1 and 2-methylcyclohexano, 4D9). The simulations demonstrate that both allosteric molecules change the PR conformation and stabilize the structures of PR and the inhibitor; the residues of the flaps are sensitive to the allosteric molecules and the flexibility of the residues is pronouncedly suppressed; the additions of the small molecules to the allosteric sites strengthen the binding affinities of 3TL-PR by about 12-15kal/mol in the binding free energy, which mainly arises from electrostatic term. Interestingly, it is found that the action mechanisms of 1F1 and 4D9 are different, the former behaviors like a doorman that keeps the inhibitor from escape and makes the flaps (door) partially open; the latter is like a wedge that expands the allosteric space and meanwhile closes the flaps. Our data provide a theoretical support for designing the allosteric inhibitor.
authors.affiliation: School of Physics and Electronics, Shandong Normal University, Jinan 250014, China.
authors.forename: Xian-Mei
authors.initials: XM
authors.lastname: Meng
authors.affiliation: School of Physics and Electronics, Shandong Normal University, Jinan 250014, China. Electronic address: huweijun@sdnu.edu.cn.
authors.forename: Wei-Jun
authors.initials: WJ
authors.lastname: Hu
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore 639815, Singapore. Electronic address: ygmu@pmail.ntu.edu.sg.
authors.forename: Yu-Guang
authors.initials: YG
authors.lastname: Mu
authors.affiliation: School of Chemistry, Shandong Normal University, Jinan 250014, China.
authors.forename: Xie-Huang
authors.initials: XH
authors.lastname: Sheng
mesh_terms: D000495:Allosteric Site; D001665:Binding Sites; D016333:HIV Protease / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D013816:Thermodynamics; D013997:Time Factors
chemical_list: D017320:HIV Protease Inhibitors; D054852:Small Molecule Libraries; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1
keywords: Allosteric inhibitor; Binding free energy; HIV-1 protease; Inhibitor; Molecular dynamics simulation