WO 1 Towards fully flexible docking

We have developed a fully flexible docking method that uses a reduced lattice representation of protein molecules, adapted for modeling peptide ligand — protein complexes. The CABS model (Carbon Alpha, Carbon Beta, Side Group) employed here was initially designed for single-chain protein folding, and performed well in many applications [Kolinski & Bujnicki, 2005]. Instead of full-atomic protein representation, the CABS model incorporates three pseudo-atoms per residue — Cα, Cβ and the center of the side group. Force field used by CABS was derived from statistical analysis of the non-redundant database of protein structures. In test applications the native state of the complex was reconstructed from separated molecules of the receptor and the peptide ligands. This was done for a set of protein complexes, for which three-dimensional structures are known, including the rat VDR vitamin D receptor bound to a short peptide mimicking its coactivator. Accuracy of obtained models [Kurcinski & Kolinski, 2007], calculated as cRMSD (coordinate Root-Mean-Square Deviation) between experimental and model structures, varied from 0.7Å up to 4Å, which is competitive with experimental methods, such as crystallography or NMR. Construction of a fast and accurate flexible docking procedure is nowadays one of the most important tasks of bioinformatics and is crucial for rational drug design. A forthcoming modeling study should lead to a better understanding of mechanisms of macromolecular assembly and explain coactivator effects on receptor activity.