A systematic study of low-resolution recognition in protein--protein complexes

Abstract

A comprehensive nonredundant database of 475 cocrystallized protein-protein complexes was used to study low-resolution recognition, which was reported in earlier docking experiments with a small number of proteins. The docking program GRAMM was used to delete the atom-size structural details and systematically dock the resulting molecular images. The results reveal the existence of the low-resolution recognition in 52% of all complexes in the database and in 76% of the 113 complexes with an interface area >4,000 A(2). Limitations of the docking and analysis tools used in this study suggest that the actual number of complexes with the low-resolution recognition is higher. However, the results already prove the existence of the low-resolution recognition on a broad scale.

Figure 1

Examples of the distribution of ligand positions. Receptors are shown in green and ligands in yellow, in the crystallographically determined position within the complex. The 100 lowest-energy ligand positions are shown in red. Matches are clustered primarily inside the binding area (a), inside and outside the binding area (b), outside the binding area (c), and not clustered (d).

Figure 2

Idealized representation of proteins. The receptor is shown in yellow and the ligand in red. Radii are calculated as the average distance of all atoms in a protein from its center of mass. The radii shown are the average radii of all receptors and ligands. The binding region is defined as the area within 10 Å of the crystallographic position of the ligand’s center of mass and is shown in green.

Figure 3

Percent of matches inside the binding area according to the energy rank. The percent is based on the inside/total ratio of the matches of a given rank (see text). Energy rank is accumulated in the histogram in groups of 10. (a) All complexes. (b) Complexes with interface of 1,000–2,000 Ų (Top), 2,000–4,000 Ų (Middle), and >4,000 Ų (Bottom).

Figure 4

Correlation of the percent of matches inside the binding area of low-energy (rank 1–100) and high-energy (rank 901–1,000) ligand positions. The percent values are calculated for every complex in the database.

Figure 5

Distribution of complexes according to the percent of matches inside the binding site. The total number of matches per complex is 1,000 (a) and 100 (b) (lowest energy matches).

Figure 6

Percent of complexes with detected low-resolution recognition. (a) All complexes. (b) Complexes with interface area 1,000–2,000 Ų (Left), 2,000–4,000 Ų (Middle), and >4,000 Ų (Right).

Figure 7

Examples of complexes with and without detected low-resolution recognition. The receptor is shown in green and the ligand in red. All structures are in the cocrystallized positions. (a) A complex with established low-resolution. Complexes without detected low-resolution recognition: disordered termini that are part of the interface (b), interwoven chains (c), an alternative binding mode with the subunit identical to the ligand shown in blue (d), helix bundles with a cylinder-like low-resolution structure (e), and a ternary complex (f).