title: Molecular dynamics simulations of HIV-1 protease monomer: Assembly of N-terminus and C-terminus into beta-sheet in water solution.
abstract: HIV-1 protease (HIV-PR) consists of two identical subunits that are united together through a four-stranded antiparallel beta-sheet formed of the peptide termini of each monomer. Since the active site exists only in the dimer, a strategy that is attracting more and more attention in inhibitor design and which may overcome the serious drug resistance caused by competitive inhibitors is to block the peptide termini of the monomer, thereby interfering with formation of the active dimer. In the present work, we performed several extensive molecular dynamics (MD) simulations of the HIV-PR monomer in water to illustrate its solvated conformation and dynamics behavior. We found that the peptide termini usually assembled into beta-sheet after several nanoseconds' simulation, and became much less flexible. This beta-sheet is stabilized by intramolecular interactions and is not easily disaggregated under the present MD simulation conditions. This transformation may be an important transition during the relaxing and equilibrating of the HIV-PR monomer in aqueous solution, and the terminal beta-sheet may be one of the major conformations of the solvated HIV-PR monomer termini in water. This work may provide new insights into the dynamics behavior and dimerization mechanism of HIV-PR, and more significantly, offer a more rational receptor model for the design and discovery of novel dimerization inhibitors than crystalline structures.
authors.affiliation: Key Laboratory of New Drugs Design and Discovery of Liaoning Province, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
authors.forename: Mao-Cai
authors.initials: MC
authors.lastname: Yan
authors.forename: Yu
authors.initials: Y
authors.lastname: Sha
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Xu-Qiong
authors.initials: XQ
authors.lastname: Xiong
authors.forename: Jin-Hong
authors.initials: JH
authors.lastname: Ren
authors.forename: Mao-Sheng
authors.initials: MS
authors.lastname: Cheng
mesh_terms: D003198:Computer Simulation; D019281:Dimerization; D016333:HIV Protease / Q000737:chemistry*; D007700:Kinetics; D008958:Models, Molecular; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D014867:Water / Q000737:chemistry
chemical_list: D014867:Water; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1