A Multifaceted Secondary Structure Mimic Based On Piperidine‐piperidinones Academic Article uri icon

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.

altmetric score

  • 0.25

author list (cited authors)

  • Xin, D., Perez, L. M., Ioerger, T. R., & Burgess, K.

citation count

  • 24

publication date

  • March 2014

publisher