Bridge water mediates nevirapine binding to wild type and Y181C HIV-1 reverse transcriptase-Evidence from molecular dynamics simulations and MM-PBSA calculations

The important role of the bridge water molecule in the binding of HIV-1 reverse transcriptase (RT) inhibitor complex was elucidated by molecular dynamics (MD) simulations using an MM-PBSA approach. Binding free energies and thermodynamic property differences for nevirapine bound to wild type and Y181C HIV-1 reverse transcriptase were investigated, and the results were compared with available experimental data. MD simulations over 3 ns revealed that the bridge water formed three characteristic hydrogen bonds to nevirapine and two residues, His235 and Leu234, in the binding pocket. The energetic derived model, which was determined from the consecutive addition of a water molecule, confirmed that only the contribution from the bridge water was essential in the binding configuration. Including this bridge water in the MM-PBSA calculations reoriented the binding energies from -32.20 to -37.65 kcal/mol and -28.07 to -29.82 kcal/mol in the wild type and Y181C HIV-1 RT, respectively. From the attractive interactions via the bridge water, His235 and Leu234 became major contributions. We found that the bridge water is the key in stabilizing the bound complex; however, in the Y181C RT complex this bridge water showed weaker hydrogen bond formation, lack of attractive force to nevirapine and lack of binding efficiency, leading to the failure of nevirapine against the Y181C HIV-1 RT. Moreover, the dynamics of Val179, Tyr181Cys, Gly-190 and Leu234 in the binding pocket showed additional attractive energetic contributions in helping nevirapine binding. These findings that the presence of a water molecule in the hydrophobic binding site plays an important role are a step towards a quantitative understanding of the character of bridge water in enzyme-inhibitor binding. This can be helpful in developing designs for novel non-nucleoside HIV-1 RT inhibitors active against the mutant enzyme. (C) 2009 Elsevier Inc. All rights reserved.