Abstract
Designing proteins with novel protein/protein binding properties can be achieved by combining the tools that have been developed independently for protein docking and protein design. We describe here the sequence‐independent generation of protein dimer orientations by protein docking for use as scaffolds in protein sequence design algorithms. To dock monomers into sequence‐independent dimer conformations, we use a reduced representation in which the side chains are approximated by spheres with atomic radii derived from known C2 symmetry‐related homodimers. The interfaces of C2‐related homodimers are usually more hydrophobic and protein core‐like than the interfaces of heterodimers; we parameterize the radii for docking against this feature to capture and recreate the spatial characteristics of a hydrophobic interface. A fast Fourier transform‐based geometric recognition algorithm is used for docking the reduced representation protein models. The resulting docking algorithm successfully predicted the wild‐type homodimer orientations in 65 out of 121 dimer test cases. The success rate increases to ∼70% for the subset of molecules with large surface area burial in the interface relative to their chain length. Forty‐five of the predictions exhibited less than 1 Å C~α~ RMSD compared to the native X‐ray structures. The reduced protein representation therefore appears to be a reasonable approximation and can be used to position protein backbones in plausible orientations for homodimer design. © 2005 Wiley Periodicals, Inc. J Comput Chem 26: 1222–1232, 2005