title: Some insights into mechanism for binding and drug resistance of wild type and I50V V82A and I84V mutations in HIV-1 protease with GRL-98065 inhibitor from molecular dynamic simulations.
abstract: The single mutations I50V, V82A and I84V are considered as the key residue mutations of the HIV-1 protease drug resistance. The rank of calculated absolute binding free energies using MM-PBSA method is in excellent agreement with experimental result. Enthalpic and entropic balance is analyzed to explain resistance in I50V and V82A having a higher entropic contribution than in the wild type (WT) complex. The reduced van der Waals energy explains the drug resistance of I84V to GRL-98065. Detailed binding free energies between GRL-98065 and individual protein residues are calculated to provide insights into the inhibitor-protein binding and drug-resistant mechanism. Our results show I50V and V82A have larger structural changes than I84V compared with WT.
authors.affiliation: College of Physics and Electronics, Shandong Normal University, 88 Wenhua East Road, Jinan 250014, PR China.
authors.forename: Guo-Dong
authors.initials: GD
authors.lastname: Hu
authors.forename: Tong
authors.initials: T
authors.lastname: Zhu
authors.forename: Shao-Long
authors.initials: SL
authors.lastname: Zhang
authors.forename: Dunyou
authors.initials: D
authors.lastname: Wang
authors.forename: Qing-Gang
authors.initials: QG
authors.lastname: Zhang
mesh_terms: D024882:Drug Resistance, Viral; D004795:Enzyme Stability; D016333:HIV Protease / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000378:metabolism / Q000494:pharmacology; D015497:HIV-1 / Q000201:enzymology*; D056004:Molecular Dynamics Simulation; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000378:metabolism / Q000494:pharmacology*; D013816:Thermodynamics
chemical_list: C522027:(2,8-dioxabicyclo(3.3.0)oct-6-yl)-N-(4-((3,4-methylenedioxyphenyl)sulfonyl-(2-methylpropyl)amino)-3-hydroxy-1-phenylbutan-2-yl) carbamate; D017320:HIV Protease Inhibitors; D050505:Mutant Proteins; D013449:Sulfonamides; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1