title: Adding diverse noncanonical backbones to rosetta: enabling peptidomimetic design.
abstract: Peptidomimetics are classes of molecules that mimic structural and functional attributes of polypeptides. Peptidomimetic oligomers can frequently be synthesized using efficient solid phase synthesis procedures similar to peptide synthesis. Conformationally ordered peptidomimetic oligomers are finding broad applications for molecular recognition and for inhibiting protein-protein interactions. One critical limitation is the limited set of design tools for identifying oligomer sequences that can adopt desired conformations. Here, we present expansions to the ROSETTA platform that enable structure prediction and design of five non-peptidic oligomer scaffolds (noncanonical backbones), oligooxopiperazines, oligo-peptoids, [Formula: see text]-peptides, hydrogen bond surrogate helices and oligosaccharides. This work is complementary to prior additions to model noncanonical protein side chains in ROSETTA. The main purpose of our manuscript is to give a detailed description to current and future developers of how each of these noncanonical backbones was implemented. Furthermore, we provide a general outline for implementation of new backbone types not discussed here. To illustrate the utility of this approach, we describe the first tests of the ROSETTA molecular mechanics energy function in the context of oligooxopiperazines, using quantum mechanical calculations as comparison points, scanning through backbone and side chain torsion angles for a model peptidomimetic. Finally, as an example of a novel design application, we describe the automated design of an oligooxopiperazine that inhibits the p53-MDM2 protein-protein interaction. For the general biological and bioengineering community, several noncanonical backbones have been incorporated into web applications that allow users to freely and rapidly test the presented protocols (http://rosie.rosettacommons.org). This work helps address the peptidomimetic community's need for an automated and expandable modeling tool for noncanonical backbones.
authors.affiliation: Department of Biology, Center for Genomics and Systems Biology, New York University, New York, New York, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Drew
authors.forename: P Douglas
authors.initials: PD
authors.lastname: Renfrew
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Craven
authors.forename: Glenn L
authors.initials: GL
authors.lastname: Butterfoss
authors.forename: Fang-Chieh
authors.initials: FC
authors.lastname: Chou
authors.forename: Sergey
authors.initials: S
authors.lastname: Lyskov
authors.forename: Brooke N
authors.initials: BN
authors.lastname: Bullock
authors.forename: Andrew
authors.initials: A
authors.lastname: Watkins
authors.forename: Jason W
authors.initials: JW
authors.lastname: Labonte
authors.forename: Michael
authors.initials: M
authors.lastname: Pacella
authors.forename: Krishna Praneeth
authors.initials: KP
authors.lastname: Kilambi
authors.forename: Andrew
authors.initials: A
authors.lastname: Leaver-Fay
authors.forename: Brian
authors.initials: B
authors.lastname: Kuhlman
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Gray
authors.forename: Philip
authors.initials: P
authors.lastname: Bradley
authors.forename: Kent
authors.initials: K
authors.lastname: Kirshenbaum
authors.forename: Paramjit S
authors.initials: PS
authors.lastname: Arora
authors.forename: Rhiju
authors.initials: R
authors.lastname: Das
authors.forename: Richard
authors.initials: R
authors.lastname: Bonneau
mesh_terms: D000465:Algorithms; D019295:Computational Biology / Q000379:methods*; D057786:Peptidomimetics / Q000737:chemistry*; D015202:Protein Engineering; D017434:Protein Structure, Tertiary; D012984:Software
chemical_list: D057786:Peptidomimetics