Free energy decomposition of protein-protein interactions

A free energy decomposition scheme has been developed and tested on antibod y-antigen and protease-inhibitor binding for which accurate experimental st ructures were available for both free and bound proteins. Using the x-ray c oordinates of the free and bound proteins, the absolute binding free energy was computed assuming additivity of three well-defined, physical processes : desolvation of the x-ray structures, isomerization of the x-ray conformat ion to a nearby local minimum in the gas-phase, and subsequent noncovalent complex formation in the gas phase. This free energy scheme, together with the Generalized Born model for computing the electrostatic solvation free e nergy, yielded binding free energies in remarkable agreement with experimen tal data. Two assumptions commonly used in theoretical treatments; viz., th e rigid-binding approximation (which assumes no conformational change upon complexation) and the neglect of vdW interactions, were found to yield larg e errors in the binding free energy. Protein-protein vdW and electrostatic interactions between complementary surfaces over a relatively large area (1 400-1700 Angstrom (2)) were found to drive antibody-antigen and protease-in hibitor binding.