De novo structure prediction and experimental characterization of folded peptoid oligomers

Peptoid molecules are biomimetic oligomers that can fold into unique three-dimensional structures. As part of an effort to advance computational design of folded oligomers, we present blind-structure predictions for three peptoid sequences using a combination of Replica Exchange Molecular Dynamics (...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2012-09, Vol.109 (36), p.14320-14325
Main Authors: Butterfoss, Glenn L., Yoo, Barney, Jaworski, Jonathan N., Chorny, Ilya, Dill, Ken A., Zuckermann, Ronald N., Bonneau, Richard, Kirshenbaum, Kent, Voelz, Vincent A.
Format: Article
Language:English
Subjects:
Amides
biomimetics
Crystal structure
Crystallography, X-Ray
Crystals
energy
Ethanol
Free energy
Models, Molecular
Molecular chains
molecular dynamics
Molecular Dynamics Simulation
Molecular structure
Molecules
Oligomers
Peptoids - chemistry
Physical Sciences
Polymers - chemistry
Polypeptides
prediction
Protein Conformation
Protein Folding
Quantum physics
Trimers
X-ray diffraction
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Summary:Peptoid molecules are biomimetic oligomers that can fold into unique three-dimensional structures. As part of an effort to advance computational design of folded oligomers, we present blind-structure predictions for three peptoid sequences using a combination of Replica Exchange Molecular Dynamics (REMD) simulation and Quantum Mechanical refinement. We correctly predicted the structure of a N-aryl peptoid trimer to within 0.2 Å rmsd-backbone and a cyclic peptoid nonamer to an accuracy of 1.0 Å rmsd-backbone. X-ray crystallographic structures are presented for a linear N-alkyl peptoid trimer and for the cyclic peptoid nonamer. The peptoid macrocycle structure features a combination of cis and trans backbone amides, significant nonplanarity of the amide bonds, and a unique "basket" arrangement of (S)-N(1-phenylethyl) side chains encompassing a bound ethanol molecule. REMD simulations of the peptoid trimers reveal that well folded peptoids can exhibit funnel-like conformational free energy landscapes similar to those for ordered polypeptides. These results indicate that physical modeling can successfully perform de novo structure prediction for small peptoid molecules.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1209945109