Membrane Protein Docking Algorithm
A wide range of fundamental biological processes are mediated by membrane proteins. Despite their large number and importance, less than 1% of all 3D protein structures deposited in the PDB are of membrane proteins. This is mainly due to the challenges of crystallizing such proteins or performing NMR analyses. All the more so, there is only small number of membrane protein-protein complexes with known structure. Therefore, developing computational tools for docking membrane proteins is crucial. Numerous methods for docking globular proteins exist, however very few have been developed especially for membrane proteins and designed to address docking within the lipid bilayer environment. We present a novel algorithm, Memdock, for docking alpha-helical membrane proteins which takes into consideration the lipid bilayer environment for docking as well as for refining and ranking the docking candidates. We show that our algorithm improves both the docking accuracy and the candidates ranking compared to algorithms which were originally designed for globular proteins.
In Memock web-server the user can upload/specify PDB codes of two PDB files (receptor and ligand). The output is a ranked list of the first 10 refined output solutions and their PDBs.
The Algorithm:
The receptor and the ligand are first docked by rigid geometric docking, with a modified version of PatchDock algorithm (ref. 2) keeping the transformation consistant with the membrane. Then each candidate is subsequently refined by modified Fiberdock algorithm (ref. 3), in which perturbations of the ligand are enforced to be in a membrane consistent orientation. The method models both side-chain and backbone flexibility and performs rigid body optimization of the ligand orientation. Finally, the refined models are re-scored and re-ranked according to an energy function that was designed specifically for membrane proteins.
References:
- Naama Hurwitz, Dina Schneidman-Duhovny and Haim J. Wolfson1 (2016) Memdock: Membrane Proteins Docking algorithm. Submitted
- D. Duhovny, R. Nussinov, and H. J. Wolfson. Efficient unbound docking of rigid molecules. In R. Guigo and D. Gusfield, editors, Workshop on Algorithms in Bioinformatics, volume 2452, pages 185-200. Springer Verlag, 2002.
- E. Mashiach, R. Nussinov and H. J. Wolfson. FiberDock: Flexible induced-fit backbone refinement in molecular docking. Proteins 2009 Dec 9;78(6):1503-1519.