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- Title
A Multifaceted Secondary Structure Mimic Based On Piperidine-piperidinones.
- Authors
Xin, Dongyue; Perez, Lisa M.; Ioerger, Thomas R.; Burgess, Kevin
- Abstract
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- 1 faf crystallized in a conformation that is estimated to be 0.91 kcal mol−1 above the minimum energy solution state.
- Subjects
PIPERIDINE; PROTEIN-protein interactions; CONFORMATIONAL analysis; COMPUTATIONAL chemistry; MOLECULAR structure; AMINO acids
- Publication
Angewandte Chemie, 2014, Vol 126, Issue 14, p3668
- ISSN
0044-8249
- Publication type
Article
- DOI
10.1002/ange.201400927