The atomic structure of protein-protein recognition sites

The non-covalent assembly of proteins that fold separately is central to ma ny biological processes, and differs from the permanent macromolecular asse mbly of protein subunits in oligomeric proteins. We performed an analysis o f the atomic structure of the recognition sites seen in 75 protein-protein complexes of known three-dimensional structure: 24 protease-inhibitor, 19 a ntibody-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 t hat occur upon association. Of the 75 complexes, 52 have "standard-size" in terfaces in which the total area buried by the components in the recognitio n site is 1600 (+/-400) Angstrom(2). In these complexes, association involv es only small changes of conformation. Twenty complexes have "large" interf aces burying 2000 to 4660 Angstrom(2), and large conformational changes are seen to occur in those cases where we can compare the structure of complex ed and free components. The average interface has approximately the same no n-polar character as the protein surface as a whole, and carries somewhat f ewer charged groups. However, some interfaces are significantly more polar and others more non-polar than the average. Of the atoms that lose accessibility upon association, half make contacts a cross the interface and one-third become fully inaccessible to the solvent. In the latter case, the Voronoi volume was calculated and compared with th at of atoms buried inside proteins. The ratio of the two volumes was 1.01 ( +/-0.03) in all but 11 complexes, which shows that atoms buried at protein- protein interfaces are close-packed like the protein interior. This conclus ion could be extended to the majority of interface atoms by including solve nt positions determined in high-resolution X-ray structures in the calculat ion of Voronoi volumes. Thus, water molecules contribute to the close-packi ng of atoms that insure complementarity between the two protein surfaces, a s well as providing polar interactions between the two proteins. (C) 1999 A cademic Press.