Soft protein-protein docking in internal coordinates

Abstract

The association of two biological macromolecules is a fundamental biological phenomenon and an unsolved theoretical problem. Docking methods for ab initio prediction of association of two independently determined protein structures usually fail when they are applied to a large set of complexes, mostly because of inaccuracies in the scoring function and/or difficulties on simulating the rearrangement of the interface residues on binding. In this work we present an efficient pseudo-Brownian rigid-body docking procedure followed by Biased Probability Monte Carlo Minimization of the ligand interacting side-chains. The use of a soft interaction energy function precalculated on a grid, instead of the explicit energy, drastically increased the speed of the procedure. The method was tested on a benchmark of 24 protein-protein complexes in which the three-dimensional structures of their subunits (bound and free) were available. The rank of the near-native conformation in a list of candidate docking solutions was <20 in 85% of complexes with no major backbone motion on binding. Among them, as many as 7 out of 11 (64%) protease-inhibitor complexes can be successfully predicted as the highest rank conformations. The presented method can be further refined to include the binding site predictions and applied to the structures generated by the structural proteomics projects. All scripts are available on the Web.

Fig. 1.

Flowchart of the docking procedure used in this work.

Fig. 2.

Representation of the near-native solutions obtained after redocking complexed subunits: (A) 1cho; root mean square deviation (RMSD), 0.3 Å; and (B) TEM1; RMSD, 1.3 Å. In red is represented the predicted ligand molecule, compared with the real structure (in gray). Only the receptor C^α atoms (in cyan) are optimally superimposed onto the corresponding atoms of the real complex. For clarity, only backbone atoms (nitrogen, C^α, and carbonyl carbon) are shown.

Fig. 3.

Representation of the near-native (in red) and lowest energy (in green) solutions after docking unbound subunits and further refinement of the ligand interface side-chains. For those complexes in which the near-native conformation was the lowest energy solution, only the latter is represented (in green). The real ligand structure is represented (in gray) for comparison. Only the receptor C^α atoms (in blue) are optimally superimposed onto the corresponding atoms of the real complex (in cyan). For clarity, only backbone atoms (nitrogen, C^α, and carbonyl carbon) are shown. The root mean square deviation (RMSD) of the near-native predicted structure respect to the real complex (calculated for the ligand interface C^α atoms when the receptor is optimally superimposed onto the real one) is indicated. (A) 1ca0, RMSD 1.2 Å; RANK 1; (B) 1cbw, RMSD 0.7 Å; RANK 1; (C) 1acb, RMSD 4.3 Å; RANK 102; (D) 1cho, RMSD 1.0 Å; RANK 1; (E) 1cgi, RMSD 3.1 Å; RANK 12; (F) 2kai, RMSD 5.5 Å; RANK 2; (G) 2sni, RMSD 2.9 Å; RANK 1; (H) 2sic, RMSD 1.9 Å; RANK 7; (I) 1cse, RMSD 2.5 Å; RANK 40; (J) 2tec, RMSD 8.1 Å; RANK 146; (K) 1taw, RMSD 2.9 Å; RANK 1; (L) 2ptc, RMSD 2.0 Å; RANK 3; (M) 3tgi, RMSD 0.8 Å; RANK 1; (N) 1brc, RMSD 1.8 Å; RANK 1; (O) 1fss, RMSD 1.7 Å; RANK 7; (P) 1bvn, RMSD 5.0 Å; RANK 7; (Q) 1bgs, RMSD 4.2 Å; RANK 212; (R) 1ay7, RMSD 6.2 Å; RANK 156; (S) TEM1, RMSD 3.1 Å; RANK 12; (T) 1ugh, RMSD 4.8 Å; RANK 9; (U) 2pcb, RMSD 3.2 Å; RANK 46; (V) 2pcf, RMSD 5.2 Å; RANK 9; (W) 1mlc, RMSD 5.1 Å; RANK 16; and (X) 1vfb, RMSD 3.1 Å; RANK 75. Complexes 1acb, 1cse, 2tec, and 1vfb present ligand backbone deformation on binding (RMSD of the unbound ligand backbone atoms in the interface >1.8 Å with respect to the complexed structure, after optimal superimposition of all ligand Cα atoms), so the indicated RMSD values for them may not reflect the accuracy of the predicted near-native conformations.

Fig. 4.

(A) Three-dimensional model of the best solution achieved for complex 3tgi after docking unbound subunits (in green) and after the refinement step (in red), compared with the crystallographic structure (in white). Only the C^α atoms of the receptor molecules have been optimally superimposed. The conformation of the interface side-chains of the best solution after rigid-body docking (in green) was very different from the crystallographic structure (in white), which contributed to its poor scoring. After refinement, the interface side-chains (in red) had the same conformation as in the crystallographic structure (in white). (B) Distribution of solutions for complex 3tgi obtained after redocking complexed molecules, after docking unbound subunits, and after interface side-chain refinement. Red line represents the best solution.