Folding Coarse-Grained Oligomer Models with PyRosetta

19 May 2022, Version 2
This content is a preprint and has not undergone peer review at the time of posting.


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. Through systematic variation of CG parameters in these models, we can investigate various folding hypotheses and generate folding principles at the CG scale to inform the design process of new foldamer chemistries. We demonstrate CG PyRosetta’s ability to identify minimum energy structures with a diverse structural search over a range of simple models and two hypothesis-driven parameter scans investigating the effects of side-chain size and internal backbone angle on secondary structure. We are able to identify several types of secondary structures from single- and double-helices to sheet-like and knot-like structures. 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.


Protein Folding
coarse-grained modeling

Supplementary materials

Supporting Information for "Folding Coarse-Grained Oligomer Models with PyRosetta"
Supplemental information detailing energy trajectory regime transitions, clustering hyperparameter selection, helix fitting, folding simulation parameters for section 3.1, foldamer chain-length selection, next-lowest energy clusters, and all RMSD vs. cluster energy plots for sections 3.2 and 3.3.


Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.