Topological scores, measures of sequence-structure compatibility, are calculated for all 1,881 single point mutants of the human immunodeficiency virus (HIV)-1 protease using a four-body statistical potential function based on Delaunay tessellation of protein structure. Comparison of the mutant topological score data with experimental data from alanine scan studies specifically on the dimer interface residues supports previous findings that 1) L97 and F99 contribute greatly to the Gibbs energy of HIV-1 protease dimerization, 2) Q2 and T4 contribute the least toward the Gibbs energy, and 3) C-terminal residues are more sensitive to mutations than those at the N-terminus. For a more comprehensive treatment of the relationship between protease structure and function, mutant topological scores are compared with the activity levels for a set of 536 experimentally synthesized protease mutants, and a significant correlation is observed. Finally, this structure-function correlation is similarly identified by examining model systems consisting of 2,015 single point mutants of bacteriophage T4 lysozyme as well as 366 single point mutants of HIV-1 reverse transcriptase and is hypothesized to be a property generally applicable to all proteins.
(c) 2006 Wiley-Liss, Inc.