Ions and inhibitors in the binding site of HIV protease: comparison of Monte Carlo simulations and the linearized Poisson-Boltzmann theory.

Proteins can be influenced strongly by the electrolyte in which they are dissolved, and we wish to model, understand, and ultimately control such ionic effects. Relatively detailed Monte Carlo (MC) ion simulations are needed to capture biologically important properties of ion channels, but a simpler treatment of ions, the linearized Poisson-Boltzmann (LPB) theory, is often used to model processes such as binding and folding, even in settings where the LPB theory is expected to be inaccurate. This study uses MC simulations to assess the reliability of the LPB theory for such a system, the constrained, anionic active site of HIV protease. We study the distributions of ions in and around the active site, as well as the energetics of displacing ions when a protease inhibitor is inserted into the active site. The LPB theory substantially underestimates the density of counterions in the active site when divalent cations are present. It also underestimates the energy cost of displacing these counterions, but the error is not consequential because the energy cost is less than kBT, according to the MC calculations. Thus, the LPB approach will often be suitable for studying energetics, but the more detailed MC approach is critical when ionic distributions and fluxes are at issue.