Study On Computational Problems Related To Protein-ligand Flexible Docking

Molecular docking is the primary tool in the field of structure-based drug design.Early docking methods treat protein as rigid body, docked with small molecule on the basisof shape complementarity. However, most of the proteins are not entirely rigid, they havecertain degrees of structural flexibility, which is the key for them to function properly.Treatment of protein structural flexibility is an important and quite challenging problem inthe field. Another import problem is the complex conformation search algorithm. Proteinmolecules have large number of degree of freedom, which is the root cause of astronomicalnumber of possible conformation. Thus, exhaustive search is infeasible and optimizedmethod must be employed.As to the complex conformation search problem, we modified the original searchalgorithm builtin RosettaLigand. We designed and implemented the so called “parallelcomplex conformation search algorithm based on pose sharing” on the platform of Rosetta3.4. The algorithm make sampling information shared inside the single docking instance aswell as between all parallel docking instances. The algorithm is tested on a test setcontaining11self docking targets, results showed that for most cases, out methodoutperformed the original RosettaLigand search algorithm.As to the treatment of protein flexibility, we followed the current common practice inthe filed: ensemble docking, by docking ligand with multiple receptor structures ratherthan one single structure. We collected candidate structures from three sources:RosettaBackrub, molecular dynamics simulation and similar crystal structures in PDB.Collected structures are clustered by QT clustering algorithm, representative structures arepicked out construct the final structure ensemble. We tested the “pose sharing” algorithmon these structure ensembles, and compared the results with that from docking usingoriginal RosttaLigand on single receptor structure, we found that ensemble docking didimproved the docking performance to some extent, especially the ensemble constructedfrom crystal structures.