Accounting for protein loop flexibility during macromolecular docking

Karine Bastard & Chantal Prévost, Laboratoire de Biochimie Théorique, Paris.
 

    Upon macromolecular association, some proteins undergo large conformational changes that can result in surface loop movements. When the Met repressor binds to DNA, an eight residue loop of Met repressor changes its hairpin conformation into a conformation that wraps around the DNA phosphate backbone. Such an examples confirm the necessity to account for induced surface remodeling during the search for interacting surfaces, by allowing the receptor to adapt to its partner in an induced fit process. 
    To address this problem, we have recently developped a new docking method, termed MC2, which takes into account the loop and side-chain movements at the protein surface during macromolecular association. The objectives of MC2 are to precisely position the ligand, predict the loop conformations that optimally interact with the ligand and adjust the side-chain conformations, in order to predict the atomic level interactions between the two partners. The loop flexibility is artificially introduced by using a multiple copy representation. Each loop copy results from ab intio construction and represents one possible main-chain conformation of the loop with rigid backbone and flexible side-chains. The ligand position, the conformation of the protein side-chains and of the loop copy side-chains are sampled by a Monte-Carlo Simulated Annealing process. The multiple copy representation and Monte Carlo simulation are coupled via the copy weights which are recalculated at the end of each Monte Carlo cycle, finally resulting in selecting a unique loop copy at the end of MC2 process. Final loop adjustments, via energy minimzation, is found to play an important role in establishing the correct energy ranking. In a test-case study, the method was able to predict the structure of the complex at the atomic level and to unambiguously predict the conformation of an interfacial loop. 
 

Reference:
Bastard K, Thureau A, Lavery R, Prevost C. Docking macromolecules with flexible segments. J.Comput.Chem. 2003 Nov 30;24(15):1910-20. 
http://www.ibpc.fr/~bastard/MC2/mc2.html