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A Multifaceted Secondary Structure Mimic Based On Piperidine‐piperidinones
Authors:Dongyue Xin  Dr. Lisa M. Perez  Prof. Thomas R. Ioerger  Prof. Kevin Burgess
Affiliation:1. Department of Chemistry, Texas A & M University, Box 30012, College Station, TX 77841‐3012 (USA);2. Laboratory for Molecular Simulation, Texas A & M University, Box 30012, College Station, TX 77842 (USA);3. Department of Computer Science, Texas A & M University, College Station, TX 77843‐3112 (USA)
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.
Keywords:amino acids  computational chemistry  helical structures  peptidomimetics  protein–  protein interactions  secondary structures
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