Computational analyses of the surface properties of protein-protein interfaces

Abstract

Several potential applications of structural biology depend on discovering how one macromolecule might recognize a partner. Experiment remains the best way to answer this question, but computational tools can contribute where this fails. In such cases, structures may be studied to identify patches of exposed residues that have properties common to interaction surfaces and the locations of these patches can serve as the basis for further modelling or for further experimentation. To date, interaction surfaces have been proposed on the basis of unusual physical properties, unusual propensities for particular amino-acid types or an unusually high level of sequence conservation. Using the CXXSurface toolkit, developed as a part of the CCP4MG program, a suite of tools to analyse the properties of surfaces and their interfaces in complexes has been prepared and applied. These tools have enabled the rapid analysis of known complexes to evaluate the distribution of (i) hydrophobicity, (ii) electrostatic complementarity and (iii) sequence conservation in authentic complexes, so as to assess the extent to which these properties may be useful indicators of probable biological function.

Figure 1

Example of a conservation-mapped molecular surface and an interfacial subset. (a) A molecular surface is generated from the CDK2 chain in a structure of the CDK2–cyclin A complex (PDB code 1qmz; Brown et al., 1999 ▶). The cyclin molecule is shown in purple and the molecular surface in grey. The peptide substrate is shown in yellow. (b) In the next step of the analysis, conservation scores calculated from a multiple sequence alignment of cdc2 functional homologues are projected onto the molecular surface. The molecular surface is now coloured in shades of red (high conservation), white (intermediate conservation) and blue (low conservation, i.e. high variability). (c) The CDK2–cyclin A interface is extracted by identifying that part of the CDK2 molecular surface that is buried by the cyclin A molecule upon complex formation.

Figure 2

Distribution of hydrophobicity around tryptophan and arginine residues. The side chains of tryptophan (a, b) and arginine (c, d) are shown in either ball-and-stick (a, c) or molecular-surface (b, d) representation. Ball-and-stick representations are coloured by atom type, whereas the surface representation is coloured by GRID-assigned hydrophobic potential. Here, yellow indicates regions with high local hydrophobicity, while purple indicates nonhydrophobic surface patches.

Figure 3

The SH3 domain of Abl tyrosine kinase (PDB code 1abo) complex surface properties and function. (a) The secondary-structure representation of the Abl tyrosine kinase, showing a typical SH3 domain. (b) A molecular-surface representation including the proline-rich ligand peptide as a ball-and-stick model. The surface is coloured by local surface hydrophobicity, with strongly hydrophobic surfaces coloured yellow and weakly hydrophobic surfaces elements coloured green.

Figure 4

Rank-ordered distribution of ΔΦ. The calculated differences between the mean hydrophobicity of interface and non-interface surfaces are plotted in ranked order. In all but 15 cases, the interfacial surface is more hydrophobic than the non-interface surface.

Figure 5

Rank-ordered distribution of electrostatic complementarity. The linear correlation coefficient of electrostatic potentials for different interacting partners is presented for 72 structures. In the vast majority of cases there is an anticorrelation of potential consistent with a marked electrostatic complementarity.