title: A molecular dynamics study of the structural stability of HIV-1 protease under physiological conditions: the role of Na+ ions in stabilizing the active site.
abstract: HIV-1 protease is most active under weakly acidic conditions (pH 3.5-6.5), when the catalytic Asp25 and Asp25' residues share 1 proton. At neutral pH, this proton is lost and the stability of the structure is reduced. Here we present an investigation of the effect of pH on the dynamics of HIV-1 protease using MD simulation techniques. MD simulations of the solvated HIV-1 protease with the Asp25/25' residues monoprotonated and deprotonated have been performed. In addition we investigated the effect of the inclusion of Na(+) and Cl(-) ions to mimic physiological salt conditions. The simulations of the monoprotonated form and deprotonated form including Na(+) show very similar behavior. In both cases the protein remained stable in the compact, "self-blocked" conformation in which the active site is blocked by the tips of the flaps. In the deprotonated system a Na(+) ion binds tightly to the catalytic dyad shielding the repulsion between the COO(-) groups. Ab initio calculations also suggest the geometry of the active site with the Na(+) bound closely resembles that of the monoprotonated case. In the simulations of the deprotonated form (without Na(+) ions), a water molecule bound between the Asp25 Asp25' side-chains. This disrupted the dimerization interface and eventually led to a fully open conformation.
authors.affiliation: Protein Engineering Department, Institute of Molecular Biology and Genetics, UAS, Kiev, Ukraine. dikov@imbg.org.ua <dikov@imbg.org.ua>
authors.forename: Dmytro
authors.initials: D
authors.lastname: Kovalskyy
authors.forename: Volodymyr
authors.initials: V
authors.lastname: Dubyna
authors.forename: Alan E
authors.initials: AE
authors.lastname: Mark
authors.forename: Alexander
authors.initials: A
authors.lastname: Kornelyuk
mesh_terms: D001224:Aspartic Acid / Q000737:chemistry; D001665:Binding Sites; D055592:Biophysical Phenomena; D001703:Biophysics; D002384:Catalysis; D019295:Computational Biology; D003198:Computer Simulation; D030562:Databases, Protein; D019281:Dimerization; D016333:HIV Protease / Q000737:chemistry*; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D007477:Ions / Q000737:chemistry*; D008958:Models, Molecular; D015233:Models, Statistical; D008968:Molecular Conformation; D017433:Protein Structure, Secondary; D040901:Proteomics / Q000379:methods*; D012964:Sodium / Q000737:chemistry*; D012984:Software
chemical_list: D007477:Ions; D001224:Aspartic Acid; D012964:Sodium; D016333:HIV Protease