title: A multifaceted secondary structure mimic based on piperidine-piperidinones.
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.
authors.affiliation: Department of Chemistry, Texas A & M University, Box 30012, College Station, TX 77841-3012 (USA).
authors.forename: Dongyue
authors.initials: D
authors.lastname: Xin
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Perez
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Ioerger
authors.forename: Kevin
authors.initials: K
authors.lastname: Burgess
mesh_terms: D000596:Amino Acids; D008958:Models, Molecular; D008968:Molecular Conformation; D010880:Piperidines / Q000737:chemistry*; D011485:Protein Binding; D017433:Protein Structure, Secondary / Q000502:physiology*
chemical_list: D000596:Amino Acids; D010880:Piperidines; C032727:piperidine
keywords: amino acids; computational chemistry; helical structures; peptidomimetics; protein-protein interactions; secondary structures