PK(A) SHIFTS IN SMALL MOLECULES AND HIV PROTEASE - ELECTROSTATICS ANDCONFORMATION

The generalized Barn (GB) approximation is a reasonable electrostatic model that is fast enough for use with extensive conformational sampli ng. This study combines the GB model with a torsion-space sampling met hod to compute pK(a) shifts for a series of dicarboxylic acids and ami no acids, and for the active-site aspartyl dyad in HIV-1 protease. The calculations agree rather well with experiment for the small molecule s Conformational analysis shows salt-bridging for the zwitterionic ami no acids but otherwise modest electrostatic effects upon mean chain le ngths. The calculations also show that through-space electrical fields alone cannot account completely for the observed pK(a) shifts. The ca lculations for HIV protease agree reasonably well with experiment, des pite the complexity of the system. The present computational approach should be useful for a variety of other applications.