期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 53, 期 14, 页码 3594-3598出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201400927
关键词
amino acids; computational chemistry; helical structures; peptidomimetics; protein-protein interactions; secondary structures
资金
- National Institutes of Health [GM087981]
- Robert A. Welch Foundation [A-1121]
Minimalist secondary structure mimics are typically made to resemble one interface in a protein-protein interaction (PPI), and thus perturb it. We recently proposed suitable chemotypes can be matched with interface regions directly, without regard for secondary structures. Here we describe a modular synthesis of a new chemotype 1, simulation of its solution-state conformational ensemble, and correlation of that with ideal secondary structures and real interface regions in PPIs. Scaffold 1 presents amino acid side-chains that are quite separated from each other, in orientations that closely resemble ideal sheet or helical structures, similar non-ideal structures at PPI interfaces, and regions of other PPI interfaces where the mimic conformation does not resemble any secondary structure. 68 different PPIs where conformations of 1 matched well were identified. A new method is also presented to determine the relevance of a minimalist mimic crystal structure to its solution conformations. Thus dld-1faf crystallized in a conformation that is estimated to be 0.91kcalmol(-1) above the minimum energy solution state.
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