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

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. Proteins 2005. © 2004 Wiley‐Liss, Inc.