A structural basis for the specificity of protein-protein recognition
Tuesday 22 June 2004, 14:00-15:00
Seminar Room 1, Newton Institute
We compare the geometric and physical chemical properties of interfaces involved in specific and non-specific protein-protein interactions in crystal structures reported in the Protein Data Bank. Specific interactions are illustrated by 70 protein-protein complexes and by subunit contacts in 122 homodimeric proteins; non-specific interactions, by 188 pairs of monomeric proteins making crystal packing contacts selected to bury more than 800 Å2 of protein surface. A majority of these pairs have two-fold symmetry and form crystal dimers that cannot be distinguished from real dimers on the basis of the interface size or symmetry. Their chemical and amino acid compositions resemble the protein solvent accessible surface, they are less hydrophobic than in homodimers and contain much fewer fully buried atoms. We develop a residue propensity score to assess preferences for the different types of interfaces, and we derive indexes to evaluate the atomic packing, which is less compact at non-specific than at specific interfaces.
These differences can be interpreted in terms of geometric and chemical complementarity in cases where conformation changes are small and recognition takes place between preformed surfaces. In contrast, large changes at an interface imply that recognition first occurs between surfaces that are not complementary. A basic question in molecular assembly is how this process takes place, and whether we can reproduce it. Molecular docking algorithms that generate protein-protein complexes based on the component structures have been tested in a blind prediction experiment called CAPRI (Critical Assessment of PRedicted Interactions). Results obtained on 13 target complexes indicate that prediction procedures often succeed when the conformation changes are small, although they fail to reproduce large changes.
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