Protein docking using continuum electrostatics and geometric fit

The computer program DOT quickly finds low-energy docked structuresfor two proteins by performing a systematic search over sixdegrees of freedom. A novel feature of DOT is its energy function,which is the sum of both a Poisson–Boltzmann electrostaticenergy and a van der Waals energy, each represented as a grid-basedcorrelation function. DOT evaluates the energy of interactionfor many orientations of the moving molecule and maintains separatelists scored by either the electrostatic energy, the van derWaals energy or the composite sum of both. The free energy isobtained by summing the Boltzmann factor over all rotationsat each grid point. Three important findings are presented.First, for a wide variety of protein–protein interactions,the composite-energy function is shown to produce larger clustersof correct answers than found by scoring with either van derWaals energy (geometric fit) or electrostatic energy alone.Second, free-energy clusters are demonstrated to be indicatorsof binding sites. Third, the contributions of electrostaticand attractive van der Waals energies to the total energy termappropriately reflect the nature of the various types of protein–proteininteractions studied.