GalaxyRefineComplex: Refinement of protein-protein complex model structures driven by interface repacking.

Lim Heo,Hasup Lee,Chaok Seok

doi:10.1038/srep32153

Lim Heo, Hasup Lee + Show 1 more

Open Access

https://doi.org/10.1038/srep32153

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Abstract

Protein-protein docking methods have been widely used to gain an atomic-level understanding of protein interactions. However, docking methods that employ low-resolution energy functions are popular because of computational efficiency. Low-resolution docking tends to generate protein complex structures that are not fully optimized. GalaxyRefineComplex takes such low-resolution docking structures and refines them to improve model accuracy in terms of both interface contact and inter-protein orientation. This refinement method allows flexibility at the protein interface and in the overall docking structure to capture conformational changes that occur upon binding. Symmetric refinement is also provided for symmetric homo-complexes. This method was validated by refining models produced by available docking programs, including ZDOCK and M-ZDOCK, and was successfully applied to CAPRI targets in a blind fashion. An example of using the refinement method with an existing docking method for ligand binding mode prediction of a drug target is also presented. A web server that implements the method is freely available at http://galaxy.seoklab.org/refinecomplex.

Highlights

Inter-protein orientation, side-chain conformation, and backbone conformation, such as loops[15]
The performance of GalaxyRefineComplex was compared with those of RosettaDock and FiberDock on the two hetero-complex sets (ZDOCK benchmark set and Critical Assessment of Prediction of Interactions (CAPRI) set) and with those of RosettaDock run with a symmetry option and SymmRef, a symmetric version of FiberDock, on the two homo-complex sets (PISA benchmark set and CAPRI set)
The CAPRI criterion reflects the biological relevance of the model structures, and model qualities are classified as high (***), medium (**), acceptable (*), and incorrect considering ligand RMSD (L-RMSD) and interface RMSD (I-RMSD) from the experimental structure and the fraction of predicted native contacts (Fnat)

Summary

Introduction

Inter-protein orientation, side-chain conformation, and backbone conformation, such as loops[15]. We introduce a new refinement method that improves less accurate protein-protein complex model structures compared to previous methods, for both hetero- and homo-complexes. This method, called GalaxyRefineComplex, was developed by extending the GalaxyRefine method for protein monomer structures[21,22]. GalaxyRefineComplex adapts the effective sampling method of GalaxyRefine by performing repetitive repacking of interface side chains followed by short MD relaxations. This sampling procedure mimics a protein-protein binding process in which side-chain interactions between two approaching proteins drive changes in the inter-protein orientation and intra-protein backbone conformation. GalaxyRefineComplex was successfully tested in a blind fashion in the CAPRI round 3026 (http://www.ebi.ac.uk/msd-srv/capri/round30/results/), which was held jointly with CASP11 (http://www.ebi.ac.uk/msd-srv/capri/round30/CAPRI_R30_v20141224.SW.pdf)

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