The major practical goal of this Project is to bring to the PPG a systematic computational modeling approach for the development of selective ligands for the PCAF bromodomain (BRD), that will bind with high affinity to the site shared with the HIV-Tat protein and inhibit its binding. The major conceptual goal of this Project is to contribute a powerful computational approach to the structure-based design paradigm developed in the PPG fiom a combination of multidisciplinary approaches. The computational component of this paradigm that we are developingand applying to the design of specific ligands for the PCAF BRD, takes advantage of combinations of state-of-the-art methods in the following areas: a) computational structural genomics and bioinformatics, for the discovery and structure-based classification of BRDs on a genomic scale; b) computational modeling and molecular biophysics for the comparison and quantification of dynamic and reactivity properties of BRD proteins and their complexes with peptides and small molecular ligands, and c) computational chemistry of small molecular systems for the quantitative analysis of conformational and molecular reactivity properties and binding affinities, to be used for the characterization and structural linking of molecular components in the construction of selective BRD ligands. The work is designed to achieve the maximal synergy inherent in the paradigm we are developing within the PPG by (i) taking full advantage of the results and insights emerging from the other two projects of the PPG (e.g., in the choice of compounds and the design of computational binding experiments, (ii) make testable predictions (e.g., of sites of ligand BRD interactions that can be tested with mutagenesis and structure determination), as well as produce mechanistic hypotheses (e.g., of new ligands and combinations of functional groups into binding compounds) to be tested experimentally in Projects #1 and #3, and (iii) support the coordinated efforts of the PPG components both directly and through the work of the two Cores of the PPG (e.g., by providing guides for ligand design).
