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Computational analyses of the surface properties of protein-protein interfaces.

Gruber J, Zawaira A, Saunders R, Barrett CP, Noble ME - Acta Crystallogr. D Biol. Crystallogr. (2006)

Bottom Line: Experiment remains the best way to answer this question, but computational tools can contribute where this fails.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.

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Affiliation: Laboratory of Molecular Biophysics, Rex Richards Building, South Parks Road, Oxford OX1 3QU, England.

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.

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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.
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fig1: 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.

Mentions: We have mapped sequence conservation onto triangulated molecular-surface representations of a protein. In addition to permitting visualization of the conservation of amino acids that form the molecular surface (e.g. Fig. 1 ▶ b), this approach has allowed us to re-evaluate the extent to which sequence conservation is a statistically significant property of protein–protein interfaces using a scoring system in which the conservation score of a residue is weighted by the surface-area contribution made by that residue to the surface of interest.


Computational analyses of the surface properties of protein-protein interfaces.

Gruber J, Zawaira A, Saunders R, Barrett CP, Noble ME - Acta Crystallogr. D Biol. Crystallogr. (2006)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2483497&req=5

fig1: 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.
Mentions: We have mapped sequence conservation onto triangulated molecular-surface representations of a protein. In addition to permitting visualization of the conservation of amino acids that form the molecular surface (e.g. Fig. 1 ▶ b), this approach has allowed us to re-evaluate the extent to which sequence conservation is a statistically significant property of protein–protein interfaces using a scoring system in which the conservation score of a residue is weighted by the surface-area contribution made by that residue to the surface of interest.

Bottom Line: Experiment remains the best way to answer this question, but computational tools can contribute where this fails.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Molecular Biophysics, Rex Richards Building, South Parks Road, Oxford OX1 3QU, England.

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.

Show MeSH