Sampling the conformation of protein surface residues for flexible protein docking

Background: The problem of determining the physical conformation of a protein dimer, given the structures of the two interacting proteins in their unbound state, is a difficult one. The location of the docking interface is determined largely by geometric complementarity, but finding complementary geometry is complicated by the flexibility of the backbone and side-chains of both proteins. We seek to generate candidates for docking that approximate the bound state well, even in cases where there is backbone and/or side-chain difference from unbound to bound states. Results: We divide the surfaces of each protein into local patches and describe the effect of side-chain flexibility on each patch by sampling the space of conformations of its side-chains. Likely positions of individual side-chains are given by a rotamer library; this library is used to derive a sample of possible mutual conformations within the patch. We enforce broad coverage of torsion space. We control the size of the sample by using energy criteria to eliminate unlikely configurations, and by clustering similar configurations, resulting in 50 candidates for a patch, a manageable number for docking. Conclusions: Using a database of protein dimers for which the bound and unbound structures of the monomers are known, we show that from the unbound patch we are able to generate candidates for docking that approximate the bound structure. In patches where backbone change is small (within 1 A RMSD of bound), we are able to account for flexibility and generate candidates that are good approximations of the bound state (82% are within 1 A and 98% are within 1.4 A RMSD of the bound conformation). We also find that even in cases of moderate backbone flexibility our candidates are able to capture some of the overall shape change. Overall, in 650 of 700 test patches we produce a candidate that is either within 1 A RMSD of the bound conformation or is closer to the bound state than the unbound is. Background This paper concerns one aspect of the problem of predicting the interface region of two docking proteins, namely the flexibility of side-chains. We consider sampling the possible side-chain conformations to improve the match of local shape complementarity. The main challenge we face is reducing the exponential complexity of the conformation space to a reasonably sized sample. Proteins are at the heart of all biological processes, and their functions are largely determined by their geometric structures. The number of biomolecular protein complexes is expected to be far more than the number of individual proteins in a given proteome; in addition, their structures are more difficult to obtain through NMR and X-ray crystallographic studies. So the difficult problem of docking, that is, the computational prediction of a protein complex from the structures of its constituent proteins, is an important focus of current research. The constituent structures may be determined experimentally or may be computed by a protein structure prediction algorithm. Docking is a difficult problem and it has received much attention [1-6]. In the docked configuration, two proteins demonstrate excellent shape complementarity, with the molecular surfaces matching each other closely over an interface region which is several square A in area. This excellent fit is difficult to find, however, since