Binding mechanisms are extremely important for protein function. Through molecular dynamics simulations, we study the path from the open to the closed form in a protein for which there are experimental data for a large conformational change. For several enzymes we have studied, a series of events emerges, consistent with experiment and with a striking correlation between conserved database positions and identified flexible regions. Despite the dissimilar structure, and function, we observe a conserved mechanism. Proteins function through binding. Our goal is to predict binding modes of protein-protein and protein-ligand sociations. Further, our goal is to predict these even if there are significant structural changes, or if the input are modeled (genomic) data. Our work is in two directions. First, to characterize binding sites in a way that is immune to the fine features of the molecular surface. And second to devise flexible docking algorithms. For the first, we study residue """"""""hot spots"""""""" on the protein surface and explore combinatorial phage display libraries. For the second, we continue the development of docking algorithms which allow hinge-bending motions.

National Institute of Health (NIH)
Division of Basic Sciences - NCI (NCI)
Intramural Research (Z01)
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Basic Sciences
United States
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Nussinov, Ruth (2013) The spatial structure of cell signaling systems. Phys Biol 10:045004
Zanuy, David; Ballano, Gema; Jimenez, Ana I et al. (2009) Protein segments with conformationally restricted amino acids can control supramolecular organization at the nanoscale. J Chem Inf Model 49:1623-9
Pan, Yongping; Nussinov, Ruth (2008) p53-Induced DNA bending: the interplay between p53-DNA and p53-p53 interactions. J Phys Chem B 112:6716-24
Keskin, Ozlem; Nussinov, Ruth; Gursoy, Attila (2008) PRISM: protein-protein interaction prediction by structural matching. Methods Mol Biol 484:505-21
Halperin, Inbal; Wolfson, Haim; Nussinov, Ruth (2006) Correlated mutations: advances and limitations. A study on fusion proteins and on the Cohesin-Dockerin families. Proteins 63:832-45
Liu, Jin; Pan, Yongping; Ma, Buyong et al. (2006) ""Similarity trap"" in protein-protein interactions could be carcinogenic: simulations of p53 core domain complexed with 53BP1 and BRCA1 BRCT domains. Structure 14:1811-21
Aleman, Carlos; Zanuy, David; Jimenez, Ana I et al. (2006) Concepts and schemes for the re-engineering of physical protein modules: generating nanodevices via targeted replacements with constrained amino acids. Phys Biol 3:S54-62
Zanuy, David; Nussinov, Ruth; Aleman, Carlos (2006) From peptide-based material science to protein fibrils: discipline convergence in nanobiology. Phys Biol 3:S80-90
Haspel, Nurit; Zanuy, David; Aleman, Carlos et al. (2006) De novo tubular nanostructure design based on self-assembly of beta-helical protein motifs. Structure 14:1137-48
Tsai, Hui-Hsu Gavin; Gunasekaran, Kannan; Nussinov, Ruth (2006) Sequence and structure analysis of parallel beta helices: implication for constructing amyloid structural models. Structure 14:1059-72

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