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Implicit flexibility in protein docking: Cross‐docking and local refinement
Author(s) -
Król Marcin,
Chaleil Raphael A. G.,
Tournier Alexander L.,
Bates Paul A.
Publication year - 2007
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.21698
Subject(s) - docking (animal) , searching the conformational space for docking , chemistry , molecular dynamics , macromolecular docking , minification , biological system , computer science , a priori and a posteriori , computational chemistry , algorithm , crystallography , binding site , biochemistry , biology , medicine , nursing , philosophy , epistemology , programming language
In previous CAPRI rounds (3–5) we showed that using MD‐generated ensembles, as inputs for a rigid‐body docking algorithm, increased our success rate, especially for targets exhibiting substantial amounts of induced fit. In recent rounds (6–11), our cross‐docking was followed by a short MD‐based local refinement for the subset of solutions with the lowest interaction energies after minimization. The above approach showed promising results for target 20, where we were able to recover 30% of native contacts for one of our submitted models. Further tests, performed a posteriori, revealed that cross‐docking approach produces more near‐native (NN) solutions but only for targets with large conformational changes upon binding. However, at the time of the blind docking experiment, these improved solutions were not chosen for the subsequent refinement, as their interaction energies after minimization ranked poorly compared with other solutions. This indicates deficiencies in the present scoring schemes that are based on interaction energies of minimized structures. Refinement MD simulations substantially increase the fraction of native contacts for NN docked solutions, but generally worsen interface and ligand RMSD. Further analysis shows that although MD simulations are able to improve sidechain packing across the interface, which results in an increased fraction of native contacts, they are not capable of improving interface and ligand backbone RMSD for NN structures beyond 1.5 and 3.5 Å, respectively, even if explicit solvent is used. Proteins 2007. © 2007 Wiley‐Liss, Inc.