Folding Coarse-Grained Oligomer Models with PyRosetta

Fobe, Theodore L.; Walker, Christopher C.; Meek, Garrett A.; Shirts, Michael R.

doi:10.1021/acs.jctc.2c00519

Folding Coarse-Grained Oligomer Models with PyRosetta

Journal Article · Fri Sep 30 00:00:00 EDT 2022 · Journal of Chemical Theory and Computation

DOI:https://doi.org/10.1021/acs.jctc.2c00519· OSTI ID:1899349

^[1]; ^[2]; Meek, Garrett A. ^[2]; ^[2]

Univ. of Colorado, Boulder, CO (United States); University of Colorado Boulder
Univ. of Colorado, Boulder, CO (United States)

Non-biological foldamers are a promising class of macromolecules that share similarities to classical biopolymers such as proteins and nucleic acids. Currently, designing novel foldamers is a non-trivial process, often involving many iterations of trial synthesis and characterization until folded structures are observed. In this work, we aim to tackle these foldamer design challenges using computational modeling techniques. We developed CG PyRosetta, an extension to the popular protein folding python package, PyRosetta, which introduces coarse-grained (CG) residues into PyRosetta, enabling the folding of toy CG foldamer models. Although these models are simplified, they can help explore overarching physical hypotheses about how oligomers can form. Through systematic variation of CG parameters in these models, we can investigate various folding hypotheses at the CG scale to inform the design process of new foldamer chemistries. In this study, we demonstrate CG PyRosetta’s ability to identify minimum energy structures with a diverse structural search over a range of simple models, as well as two hypothesis-driven parameter scans investigating the effects of side-chain size and internal backbone angle on secondary structures. We are able to identify several types of secondary structures from single- and double-helices to sheet-like and knot-like structures. Here, we show how side-chain size and backbone bond angle both play an important role in the structure and energetics of these toy models. Optimal side-chain sizes promote favorable packing of side chains, while specific backbone bond angles influence the specific helix type found in folded structures.

View Accepted Manuscript (DOE)

Research Organization:: Univ. of Colorado, Boulder, CO (United States)

Sponsoring Organization:: National Science Foundation (NSF); USDOE Office of Science (SC), Basic Energy Sciences (BES). Materials Sciences & Engineering Division

Grant/Contract Number:: SC0018651

OSTI ID:: 1899349

Journal Information:: Journal of Chemical Theory and Computation, Journal Name: Journal of Chemical Theory and Computation Journal Issue: 10 Vol. 18; ISSN 1549-9618

Publisher:: American Chemical SocietyCopyright Statement

Country of Publication:: United States

Language:: English

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36 MATERIALS SCIENCE
Rosetta
chemical structure
cluster chemistry
cluster structure
computational molecular design
energy
foldamers

Folding Coarse-Grained Oligomer Models with PyRosetta

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