Principles of flexible protein-protein docking

Abstract

Treating flexibility in molecular docking is a major challenge in cell biology research. Here we describe the background and the principles of existing flexible protein-protein docking methods, focusing on the algorithms and their rational. We describe how protein flexibility is treated in different stages of the docking process: in the preprocessing stage, rigid and flexible parts are identified and their possible conformations are modeled. This preprocessing provides information for the subsequent docking and refinement stages. In the docking stage, an ensemble of pre-generated conformations or the identified rigid domains may be docked separately. In the refinement stage, small-scale movements of the backbone and side-chains are modeled and the binding orientation is improved by rigid-body adjustments. For clarity of presentation, we divide the different methods into categories. This should allow the reader to focus on the most suitable method for a particular docking problem.

Figure 1

Protein flexibility types. (a,b) Shear motion, demonstrated in two conformations of S100 Calcium sensor (PDB-id: 1K9P, 1K9K). The blue helix “slides” on the rest of the protein. (c,d) Hinge motion, demonstrated in two conformations of LAO binding protein (PDB-id: 1LAO, 1LAF). The hinge location is shown as a green sphere. (e) Flexible loop in the ribosomal protein L1 (PDB-id: 1FOX). The different conformations of the loop were determined experimentally by NMR.

Figure 2

A general scheme of flexible docking procedure. (a) Protein flexibility analysis methods are described in section 2. (b) Rigid docking with soft interface, ensemble docking of different conformations and backbone refinement methods are described in section 3. (c) Side-chain refinement methods are described in section 4. (d) Rigid body optimization methods are mentioned in the discussion.

Figure 3

An example of a simplified spring model generated from a short polypeptide chain by connecting every pair of C_α atoms within a distance threshold by a spring. (a) The polypeptide chain. (b) The spring model. The normal modes calculated from this spring model describe its possible movements around the equilibrium conformation. Normal modes were shown to correlate with experimentally observed conformational changes of proteins.

Figure 4

(a) The unbound conformation of Replication Protein A in red and blue (PDB-id: 1FGU) and its target DNA strand in green. The figure shows the unbound conformation of the protein after superimposing it on its bound conformation in the solved complex structure (The superpostion was performed for visualization purpose only). (b) The bound conformation of Replication Protein A in red and blue (PDB-id: 1JMC) and the predicted bound conformation by FlexDock in cyan.

Figure 5

A correct prediction of a hot-spot residue (Arg15) by the FireDock side-chain optimization.

Figure 6. Split DEE

All possible conformations are divided into two subsets by fixing the rotamer of residue k to v1 or v2. For residue i the rotamer t1 dominates the rotamer r in the first subset of conformations. For the second subset, the rotamer t2 has a lower energy than r. Therefore, rotamer r which could not be eliminated by regular DEE, can be removed by split DEE.

Figure 7

(a) Residue interaction graph. (b) SCWRL biconnected components: abcd and def with articulation point d. The SCWRL algorithm can start by optimizing the component def. For each rotamer of d, the GMEC of def is calculated while d is fixed. After this calculation the component def is collapsed into the rotamers of d. (c) SCATD tree decomposition. The articulation points are presented on the edges.

Figure 8

A summary of methods for handling flexibility during docking, which are reviewed in the paper. The methods handle various flexibility types and are used in different stages of the docking process. Docking applications which implement the algorithmic methods are in brackets.