FireDock: Fast interaction refinement in molecular docking

Abstract

Here, we present FireDock, an efficient method for the refinement and rescoring of rigid-body docking solutions. The refinement process consists of two main steps: (1) rearrangement of the interface side-chains and (2) adjustment of the relative orientation of the molecules. Our method accounts for the observation that most interface residues that are important in recognition and binding do not change their conformation significantly upon complexation. Allowing full side-chain flexibility, a common procedure in refinement methods, often causes excessive conformational changes. These changes may distort preformed structural signatures, which have been shown to be important for binding recognition. Here, we restrict side-chain movements, and thus manage to reduce the false-positive rate noticeably. In the later stages of our procedure (orientation adjustments and scoring), we smooth the atomic radii. This allows for the minor backbone and side-chain movements and increases the sensitivity of our algorithm. FireDock succeeds in ranking a near-native structure within the top 15 predictions for 83% of the 30 enzyme-inhibitor test cases, and for 78% of the 18 semiunbound antibody-antigen complexes. Our refinement procedure significantly improves the ranking of the rigid-body PatchDock algorithm for these cases. The FireDock program is fully automated. In particular, to our knowledge, FireDock's prediction results are comparable to current state-of-the-art refinement methods while its running time is significantly lower. The method is available at http://bioinfo3d.cs.tau.ac.il/FireDock/.

Mutational Analysis Identifies Residues Crucial for Homodimerization of Myeloid Differentiation Factor 88 (MyD88) and for Its Function in Immune Cells

“…Finally, the remaining dimers were ranked according to a geometric shape complementarity score. Twenty solutions from PatchDock were further refined using the FireDock algorithm (35,36). Each dimer was refined by restricted interface side chain rearrangement and by soft rigid-body optimization.…”

A flexible docking scheme to explore the binding selectivity of PDZ domains

“…On the other hand, modeling of receptor flexibility is still a challenging problem due to the need of large conformational space that must be sampled. In order to overcome this challenge, multiple receptor conformations (MRCs) are generated in several ways: (i) using multiple conformations from molecular dynamics (MD) snapshots, [8][9][10][11][12][13] (ii) applying principal component analysis to MD trajectories, 14 (iii) using the snapshots based on geometrybased simulation techniques, 15 (iv) detecting rigid and hinge regions with the Gaussian Network Model and the Elastic Network Model (ENM), respectively, 16,17 (v) perturbing receptor conformations along different normal modes directions, [18][19][20][21] (vi) using normal modes as additional flexible variables during docking simulations, [22][23][24][25] and (vii) using multiple structures of the protein receptor obtained from experimental studies, for example X-ray crystallography or NMR analysis. [26][27][28] The majority of these types of approaches are very computationally intensive.…”

The Solution Structures of Two Human IgG1 Antibodies Show Conformational Stability and Accommodate Their C1q and FcγR Ligands

“…To dock the Fc region with the C1q head, the Web server algorithm PatchDock (version beta 1.3) (36) was used in order to take advantage of its ability to include specified residues as potential binding sites. Its output was refined using FireDock from the same Web site (37).…”