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. Proteins 2005;58:450 -458.

A diverse view of protein dynamics from NMR studies of HIV‐1 protease flaps

“…For example, irrespective of the simulation predictions of either semi-open forms or curled forms, the generalized order parameters derived from the simulations qualitatively reproduce those derived from NMR relaxation data. 14,22 In addition, both the curled or semi-open models qualitatively satisfy the characteristic b-hairpin 1 H-1 H intrasubunit NOEs observed in the previous 15 N-edited NOESY experiments 29 because the flaps mostly form a b-hairpin conformation in both models.…”

Flap flexibility amongst plasmepsins I, II, III, IV, and V: Sequence, structural, and molecular dynamics analyses

“…The most commonly used metric to measure various flap confirmations is based on the distance between the Cα of Ile50 and Ile149 . This parameter alone does not adequately describe the curling or twisting motion observed in HIV protease, which has led to the introduction of additional parameters to more accurately describe flap motions and dynamics . The flap dynamics of HIV protease highlights the significance of defining more suitable parameters that best describe flap dynamics for plasmepsins.…”

Insights into a Mutation-Assisted Lateral Drug Escape Mechanism from the HIV-1 Protease Active Site

“…A mechanism of lateral dissociation in alternative protonation states has not been reported in the literature, nor in our own studies of the protease in the monoprotonated state, in which no lateral motion is observed over a time scale of 10 ns (see Results and Supporting Information). As any protonation of the dyad most likely occurs upon or after ligand binding (36), our work shows that the G48V mutation is able to take advantage of the dianionic state of the protease to confer drug resistance through the expulsion mechanism described here.…”