09:00 to 10:00 JM Thornton ([European Bioinformatics Inst.])Protein-protein interactions from a structural perspectiveSession: Protein-Protein Interactions in Vitro and in Vivo An update of the structural features of multimeric proteins will be presented. We have compiled low redundancy sets of homomeric proteins with different symmetry and subunit composition as well as sets of heteromeric proteins for comparison. We find significant variations between monomers and multimers and with the additional data we compare dimers, trimers, tetramers and hexamers. The variations we observe can all be seen as consequences of the hydrophobic effect, which has long been noted as a major driving force in protein folding and association. A comparison with transient complexes will also be presented. Ponstingl, H., Kabir, T. & Thornton, J.M. (2003) Automatic Inference of Protein Quaternary Structure from Crystals. J. Appl. Cryst. 36, 1116-1122. Nooren, I.M.A. & Thornton, J.M. (2003a) Structural characterisation and functional significance of transient protein-protein interactions J. Mol. Biol. 325, 991-1018. PMID: 12527304 Nooren, I. & Thornton, J.M. (2003b) Diversity of protein-protein interactions. EMBO Journal. 22, 3486-3492. PMID: 12853464 INI 1 10:00 to 11:00 Random energy models for interactions and dynamics in the immune response to viruses, vaccines, and cancerSession: Protein-Protein Interactions in Vitro and in Vivo The adaptive vertebrate immune system is a wonder of modern evolution. Under most circumstances, the dynamics of the immune system is well-matched to the dynamics of pathogen growth during a typical infection. Some pathogens, however, have evolved escape mechanisms that interact in subtle ways with the immune system dynamics. In addition, negative interactions the immune system, which has evolved over 400 000 000 years, and vaccination, which has been practiced for only 200 years, are possible. For example, vaccination against the flu can actually increase susceptibility to the flu in the next year. As another example, vaccination against one of the four strains of dengue fever typically increases susceptibility against the other three strains. Immunodominance also arises in the immune system control of nascent tumors--the immune system recognizes only a small subset of the tumor specific antigens, and the rest are free to grow and cause tumor growth. In this talk, I present a physical theory of original antigenic sin and immunodominance. How localization in the immune system leads to the observed phenomena is discussed. 1) M. W. Deem and H. Y. Lee, Sequence Space Localization in the Immune System Response to Vaccination and Disease,'' Phys. Rev. Lett. 91 (2003) 068101. 2) J.-M. Park and M. W. Deem, Correlations in the T Cell Response to Altered Peptide Ligands,'' Physica A, to appear. INI 1 11:30 to 12:30 Domain interactions in multi-domain proteinsSession: Protein-Protein Interactions in Vitro and in Vivo Two thirds of all prokaryote proteins, and eighty percent of eukaryote proteins are multi-domain proteins. The composition and interaction of the domains within a multi- domain protein determine its function. Using structural assignments to the proteins in completely sequenced genomes, we have insight into the domain architectures of a large fraction of all multi-domain proteins. Thus we can investigate the patterns of pairwise domain combinations, as well as the existence of evolutionary units larger than individual protein domains. Structural assignments provide us with the sequential arrangement of domains along a polypeptide chain. In order to fully understand the structure and function of a multi-domain protein, we also need to know the geometry of the domains relative to each other in three dimensions. By studying multi-domain proteins of known three- dimensional structure, we can gain insight into the conservation of domain geometry, and the prediction of the structures of domain assemblies. INI 1 14:00 to 15:00 J Janin ([CNRS])A structural basis for the specificity of protein-protein recognitionSession: Protein-Protein Interactions in Vitro and in Vivo 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. References: The structural basis of macromolecular recognition. S.W. Wodak & J. Janin (2002) Adv. Prot. Chem. 61 9-68. Dissecting protein-protein recognition sites. P. Chakrabarti & J. Janin (2002) Proteins 47, 334-343 Dissecting protein-protein interfaces in homodimeric proteins. R.P. Bahadur, P. Chakrabarti, F. Rodier & J. Janin (2003) Proteins 53, 708-719 A dissection of specific and non-specific protein-protein interfaces. R P Bahadur, P Chakrabarti, F Rodier & J Janin (2004) J. Mol. Biol. 336, 943-955 INI 1 16:00 to 17:00 TM Truskett ([Texas, Austin])Towards a simple coarse-grained strategy for modelling unfolding, phase separation, and aggregation in protein solutionsSession: Protein-Protein Interactions in Vitro and in Vivo Protein stability, aggregation, and crystallization are of fundamental scientific and technological importance. However, molecularly-detailed models that can account for both the proteins and the solvent are computationally prohibitive to study under relevant solution conditions. As a result, the relations between misfolding/aggregation events in solution and protein sequence (mutations), solvent conditions, solution composition, and the presence of interfaces are still poorly understood. Here, we introduce a strategy for investigating these phenomena through use of a new coarse-grained model that combines an analytical theory for heteropolymer collapse with a recently introduced model for solvation in aqeuous solution. This approach can qualitatively reproduce the basic effects of temperature, pressure, and sequence on protein stability. We have used the model to derive effective center-to-center interactions for native and denatured proteins. We are currently using these effective interactions as inputs to liquid-state theory and simulation to gain new insights into the global experimental behavior of protein solutions. INI 1