Interpreting trends in the binding of cyclic ureas to HIV-1 protease

The design of new HIV protease inhibitors requires an improved understandin g of the physical basis of inhibitor/protein binding. Here, the binding aff inities of seven aliphatic cyclic ureas to HIV-1 protease are calculated us ing a predominant states method and an implicit solvent model based upon fi nite difference solutions of the Poisson-Boltzmann equation. The calculatio ns are able to reproduce the observed U-shaped trend of binding free energy as a function of aliphatic chain length. Interestingly, the decrease in af finity for the longest chains is attributable primarily to the energy cost of partly desolvating charged aspartic and arginine groups at the mouths of the active site. Even aliphatic chains too short to contact these charged groups directly are subject to considerable desolvation penalties. We are n ot aware of other systems where binding affinity trends have been attribute d to long-ranged electrostatic desolvation of ionized groups. A generalized Born/surface area solvation model yields a much smaller change in desolvat ion energy with chain length and, therefore, does not reproduce the experim ental binding affinity trends. This result suggests that the generalized Bo rn model should be used with caution for complex, partly desolvated systems like protein binding sites. We also find that changing the assumed protona tion state of the active site aspartyl dyad significantly affects the compu ted binding affinity trends. The protonation state of the aspartyl dyad in the presence of cyclic ureas is discussed in light of the observation that the monoprotonated state reproduces the experimental results best. (C) 2001 Academic Press.