The non-covalent assembly of proteins that fold separately is central to many biological processes, and differs from the permanent macromolecu-lar assembly of protein subunits in oligomeric proteins. We performed an analysis of the atomic structure of the recognition sites seen in 75 pro-tein-protein complexes of known three-dimensional structure: 24 pro-tease-inhibitor, 19 antibody-antigen and 32 other complexes, including nine enzyme-inhibitor and 11 that are involved in signal transduction. The size of the recognition site is related to the conformational changes that occur upon association. Of the 75 complexes, 52havstandard-size'' interfaces in which the total area buried by the components in the recog-nition site is 1600 (AE400) A Ê 2 . In these complexes, association involves only small changes of conformation. Twenty complexeshavlarge'' interfaces burying 2000 to 4660 A Ê 2 , and large conformational changes are seen to occur in those cases where we can compare the structure of complexed and free components. The average interface has approximately the same non-polar character as the protein surface as a whole, and carries some-what fewer charged groups. However, some interfaces are signi®cantly more polar and others more non-polar than the average. Of the atoms that lose accessibility upon association, half make contacts across the interface and one-third become fully inaccessible to the solvent. In the latter case, the Voronoi volume was calculated and compared with that of atoms buried inside proteins. The ratio of the two volumes was 1.01 (AE0.03) in all but 11 complexes, which shows that atoms buried at protein-protein interfaces are close-packed like the protein interior. This conclusion could be extended to the majority of interface atoms by includ-ing solvent positions determined in high-resolution X-ray structures in the calculation of Voronoi volumes. Thus, water molecules contribute to the close-packing of atoms that insure complementarity between the two pro-tein surfaces, as well as providing polar interactions between the two pro-teins.
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