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|2005 ||Kovalskyy, D., Dubyna, V., Mark, A. E. and Kornelyuk, A. (2005) 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. Proteins-structure Function And Bioinformatics, 58 2: 450-458.|
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. (C) 2004 Wiley-Liss, Inc.
| Professor Alan Mark|
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|Keywords: ||Biochemistry & Molecular Biology, Biophysics, HIV-1 protease, molecular dynamics, acidic and neutral pH, positive ions, stabilizing factor, ab initio optimization, Immunodeficiency Virus-1 Protease, Magnetic-resonance Relaxation, Catalytic Aspartyl Groups, Free-energy Calculations, Model-free Approach, Ab-initio, Inhibitor Binding, Orbital Methods, Retroviral Proteases, Chemical Mechanism|