Folding Coarse-Grained Oligomer Models with PyRosetta
Abstract
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 sizemore »
- Authors:
-
- Univ. of Colorado, Boulder, CO (United States)
- Publication Date:
- Research Org.:
- Univ. of Colorado, Boulder, CO (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES). Materials Sciences & Engineering Division; National Science Foundation (NSF)
- OSTI Identifier:
- 1899349
- Grant/Contract Number:
- SC0018651; ACI-1548562
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Journal of Chemical Theory and Computation
- Additional Journal Information:
- Journal Volume: 18; Journal Issue: 10; Related Information: https://github.com/shirtsgroup/cg_pyrosetta; Journal ID: ISSN 1549-9618
- Publisher:
- American Chemical Society
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 36 MATERIALS SCIENCE; Rosetta; foldamers; computational molecular design; chemical structure; cluster chemistry; cluster structure; energy
Citation Formats
Fobe, Theodore L., Walker, Christopher C., Meek, Garrett A., and Shirts, Michael R. Folding Coarse-Grained Oligomer Models with PyRosetta. United States: N. p., 2022.
Web. doi:10.1021/acs.jctc.2c00519.
Fobe, Theodore L., Walker, Christopher C., Meek, Garrett A., & Shirts, Michael R. Folding Coarse-Grained Oligomer Models with PyRosetta. United States. https://doi.org/10.1021/acs.jctc.2c00519
Fobe, Theodore L., Walker, Christopher C., Meek, Garrett A., and Shirts, Michael R. Fri .
"Folding Coarse-Grained Oligomer Models with PyRosetta". United States. https://doi.org/10.1021/acs.jctc.2c00519. https://www.osti.gov/servlets/purl/1899349.
@article{osti_1899349,
title = {Folding Coarse-Grained Oligomer Models with PyRosetta},
author = {Fobe, Theodore L. and Walker, Christopher C. and Meek, Garrett A. and Shirts, Michael R.},
abstractNote = {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.},
doi = {10.1021/acs.jctc.2c00519},
journal = {Journal of Chemical Theory and Computation},
number = 10,
volume = 18,
place = {United States},
year = {Fri Sep 30 00:00:00 EDT 2022},
month = {Fri Sep 30 00:00:00 EDT 2022}
}
Works referenced in this record:
A Field Guide to Foldamers
journal, December 2001
- Hill, David J.; Mio, Matthew J.; Prince, Ryan B.
- Chemical Reviews, Vol. 101, Issue 12
Foldamers: A Manifesto
journal, April 1998
- Gellman, Samuel H.
- Accounts of Chemical Research, Vol. 31, Issue 4
Therapeutic Potential of Foldamers: From Chemical Biology Tools To Drug Candidates?
journal, July 2016
- Gopalakrishnan, Ranganath; Frolov, Andrey I.; Knerr, Laurent
- Journal of Medicinal Chemistry, Vol. 59, Issue 21
De novo design and in vivo activity of conformationally restrained antimicrobial arylamide foldamers
journal, April 2009
- Choi, Sungwook; Isaacs, Andre; Clements, Dylan
- Proceedings of the National Academy of Sciences, Vol. 106, Issue 17
De Novo Design of Antimicrobial Polymers, Foldamers, and Small Molecules: From Discovery to Practical Applications
journal, January 2010
- Tew, Gregory N.; Scott, Richard W.; Klein, Michael L.
- Accounts of Chemical Research, Vol. 43, Issue 1
A Rationally Designed Aldolase Foldamer
journal, January 2009
- Müller, Manuel M.; Windsor, Matthew A.; Pomerantz, William C.
- Angewandte Chemie International Edition, Vol. 48, Issue 5
Folded biomimetic oligomers for enantioselective catalysis
journal, August 2009
- Maayan, G.; Ward, M. D.; Kirshenbaum, K.
- Proceedings of the National Academy of Sciences, Vol. 106, Issue 33
Foldamer-Based Molecular Recognition
journal, March 2000
- Prince, Ryan B.; Barnes, Stephanie A.; Moore, Jeffrey S.
- Journal of the American Chemical Society, Vol. 122, Issue 12
Biomimetic Nanostructures: Creating a High-Affinity Zinc-Binding Site in a Folded Nonbiological Polymer
journal, July 2008
- Lee, Byoung-Chul; Chu, Tammy K.; Dill, Ken A.
- Journal of the American Chemical Society, Vol. 130, Issue 27
Free-floating ultrathin two-dimensional crystals from sequence-specific peptoid polymers
journal, April 2010
- Nam, Ki Tae; Shelby, Sarah A.; Choi, Philip H.
- Nature Materials, Vol. 9, Issue 5
β-Peptides: From Structure to Function
journal, October 2001
- Cheng, Richard P.; Gellman, Samuel H.; DeGrado, William F.
- Chemical Reviews, Vol. 101, Issue 10
Helices and other secondary structures of β- and γ-peptides
journal, January 2006
- Seebach, Dieter; Hook, David F.; Glättli, Alice
- Biopolymers, Vol. 84, Issue 1
A Peptoid Square Helix via Synergistic Control of Backbone Dihedral Angles
journal, June 2017
- Gorske, Benjamin C.; Mumford, Emily M.; Gerrity, Charles G.
- Journal of the American Chemical Society, Vol. 139, Issue 24
Toward the Synthesis of Artificial Proteins
journal, May 2002
- Burkoth, Timothy S.; Beausoleil, Eric; Kaur, Surinder
- Chemistry & Biology, Vol. 9, Issue 5
Oligooxopiperazines as Nonpeptidic α-Helix Mimetics
journal, March 2010
- Tošovská, Petra; Arora, Paramjit S.
- Organic Letters, Vol. 12, Issue 7
A γ-Amino Acid That Favors 12/10-Helical Secondary Structure in α/γ-Peptides
journal, October 2014
- Giuliano, Michael W.; Maynard, Stacy J.; Almeida, Aaron M.
- Journal of the American Chemical Society, Vol. 136, Issue 42
Impact of γ-Amino Acid Residue Preorganization on α/γ-Peptide Foldamer Helicity in Aqueous Solution
journal, August 2016
- Fisher, Brian F.; Gellman, Samuel H.
- Journal of the American Chemical Society, Vol. 138, Issue 34
Metal-Coordination-Assisted Folding and Guest Binding in Helical Aromatic Oligoamide Molecular Capsules
journal, May 2017
- Horeau, Maxime; Lautrette, Guillaume; Wicher, Barbara
- Angewandte Chemie International Edition, Vol. 56, Issue 24
Single helically folded aromatic oligoamides that mimic the charge surface of double-stranded B-DNA
journal, April 2018
- Ziach, Krzysztof; Chollet, Céline; Parissi, Vincent
- Nature Chemistry, Vol. 10, Issue 5
Non-haemolytic β-amino-acid oligomers
journal, April 2000
- Porter, Emilie A.; Wang, Xifang; Lee, Hee-Seung
- Nature, Vol. 404, Issue 6778
Designing Helical Molecular Capsules Based on Folded Aromatic Amide Oligomers
journal, March 2018
- Ferrand, Yann; Huc, Ivan
- Accounts of Chemical Research, Vol. 51, Issue 4
Molecular Recognition within the Cavity of a Foldamer Helix Bundle: Encapsulation of Primary Alcohols in Aqueous Conditions
journal, March 2017
- Collie, Gavin W.; Bailly, Remy; Pulka-Ziach, Karolina
- Journal of the American Chemical Society, Vol. 139, Issue 17
Solid Phase Synthesis of Aromatic Oligoamides: Application to Helical Water-Soluble Foldamers
journal, October 2010
- Baptiste, Benoît; Douat-Casassus, Céline; Laxmi-Reddy, Katta
- The Journal of Organic Chemistry, Vol. 75, Issue 21
Improving Foldamer Synthesis through Protecting Group Induced Unfolding of Aromatic Oligoamides
journal, October 2006
- Zhang, Aimin; Ferguson, Joseph S.; Yamato, Kazuhiro
- Organic Letters, Vol. 8, Issue 22
Protocol for the Solid-phase Synthesis of Oligomers of RNA Containing a 2'-O-thiophenylmethyl Modification and Characterization via Circular Dichroism
journal, July 2017
- Francis, Andrew J.; Resendiz, Marino J. E.
- Journal of Visualized Experiments, Issue 125
Rosetta3: An Object-Oriented Software Suite for the Simulation and Design of Macromolecules
book, January 2011
- Leaver-Fay, Andrew; Tyka, Michael; Lewis, Steven M.
- Computer Methods, Part C
Assembly of protein tertiary structures from fragments with similar local sequences using simulated annealing and bayesian scoring functions
journal, April 1997
- Simons, Kim T.; Kooperberg, Charles; Huang, Enoch
- Journal of Molecular Biology, Vol. 268, Issue 1
Enhancing fragment-based protein structure prediction by customising fragment cardinality according to local secondary structure
journal, May 2020
- Abbass, Jad; Nebel, Jean-Christophe
- BMC Bioinformatics, Vol. 21, Issue 1
A Smoothed Backbone-Dependent Rotamer Library for Proteins Derived from Adaptive Kernel Density Estimates and Regressions
journal, June 2011
- Shapovalov, Maxim V.; Dunbrack, Roland L.
- Structure, Vol. 19, Issue 6
Homology modeling using parametric alignment ensemble generation with consensus and energy-based model selection
journal, August 2006
- Chivian, Dylan; Baker, David
- Nucleic Acids Research, Vol. 34, Issue 17
Structure prediction for CASP8 with all-atom refinement using Rosetta
journal, January 2009
- Raman, Srivatsan; Vernon, Robert; Thompson, James
- Proteins: Structure, Function, and Bioinformatics, Vol. 77, Issue S9
The Rosetta All-Atom Energy Function for Macromolecular Modeling and Design
journal, May 2017
- Alford, Rebecca F.; Leaver-Fay, Andrew; Jeliazkov, Jeliazko R.
- Journal of Chemical Theory and Computation, Vol. 13, Issue 6
Improved protein structure refinement guided by deep learning based accuracy estimation
journal, February 2021
- Hiranuma, Naozumi; Park, Hahnbeom; Baek, Minkyung
- Nature Communications, Vol. 12, Issue 1
Protein Structure Prediction Using Rosetta
book, January 2004
- Rohl, Carol A.; Strauss, Charlie E. M.; Misura, Kira M. S.
- Methods in Enzymology
FoldamerDB: a database of peptidic foldamers
journal, November 2019
- Nizami, Bilal; Bereczki-Szakál, Dorottya; Varró, Nikolett
- Nucleic Acids Research
Helical arylamide foldamers: structure prediction by molecular dynamics simulations
journal, January 2015
- Liu, Zhiwei; Abramyan, Ara M.; Pophristic, Vojislava
- New Journal of Chemistry, Vol. 39, Issue 5
Foldamer dynamics expressed via Markov state models. I. Explicit solvent molecular-dynamics simulations in acetonitrile, chloroform, methanol, and water
journal, September 2005
- Elmer, Sidney P.; Park, Sanghyun; Pande, Vijay S.
- The Journal of Chemical Physics, Vol. 123, Issue 11
De novo structure prediction and experimental characterization of folded peptoid oligomers
journal, August 2012
- Butterfoss, G. L.; Yoo, B.; Jaworski, J. N.
- Proceedings of the National Academy of Sciences, Vol. 109, Issue 36
Peptoid conformational free energy landscapes from implicit-solvent molecular simulations in AMBER
journal, December 2010
- Voelz, Vincent A.; Dill, Ken A.; Chorny, Ilya
- Biopolymers, Vol. 96, Issue 5
Evaluating the Conformations and Dynamics of Peptoid Macrocycles
journal, July 2022
- Eastwood, James R. B.; Jiang, Linhai; Bonneau, Richard
- The Journal of Physical Chemistry B, Vol. 126, Issue 28
Predicting Order and Disorder for β-Peptide Foldamers in Water
journal, September 2014
- Németh, Lukács J.; Hegedüs, Zsófia; Martinek, Tamás A.
- Journal of Chemical Information and Modeling, Vol. 54, Issue 10
Zipper-Featured δ-Peptide Foldamers Driven by Donor−Acceptor Interaction. Design, Synthesis, and Characterization
journal, December 2003
- Zhao, Xin; Jia, Mu-Xin; Jiang, Xi-Kui
- The Journal of Organic Chemistry, Vol. 69, Issue 2
Foldamer Architectures of Triazine-Based Sequence-Defined Polymers Investigated with Molecular Dynamics Simulations and Enhanced Sampling Methods
journal, October 2019
- Ahn, Surl-Hee; Grate, Jay W.
- The Journal of Physical Chemistry B, Vol. 123, Issue 44
Interplay of secondary and tertiary folding in abiotic foldamers
journal, January 2019
- Mazzier, Daniela; De, Soumen; Wicher, Barbara
- Chemical Science, Vol. 10, Issue 29
Derivation of coarse-grained potentials via multistate iterative Boltzmann inversion
journal, June 2014
- Moore, Timothy C.; Iacovella, Christopher R.; McCabe, Clare
- The Journal of Chemical Physics, Vol. 140, Issue 22
Dynamic force matching: A method for constructing dynamical coarse-grained models with realistic time dependence
journal, April 2015
- Davtyan, Aram; Dama, James F.; Voth, Gregory A.
- The Journal of Chemical Physics, Vol. 142, Issue 15
Protein modeling and structure prediction with a reduced representation.
journal, June 2004
- Kolinski, Andrzej
- Acta Biochimica Polonica, Vol. 51, Issue 2
Perspective: Coarse-grained models for biomolecular systems
journal, September 2013
- Noid, W. G.
- The Journal of Chemical Physics, Vol. 139, Issue 9
Toy amphiphiles on the computer: What can we learn from generic models?
journal, May 2009
- Schmid, Friederike
- Macromolecular Rapid Communications, Vol. 30, Issue 9-10
A lattice statistical mechanics model of the conformational and sequence spaces of proteins
journal, October 1989
- Lau, Kit Fun; Dill, Ken A.
- Macromolecules, Vol. 22, Issue 10
A test of lattice protein folding algorithms.
journal, January 1995
- Yue, K.; Fiebig, K. M.; Thomas, P. D.
- Proceedings of the National Academy of Sciences, Vol. 92, Issue 1
Practically Useful: What the R osetta Protein Modeling Suite Can Do for You
journal, April 2010
- Kaufmann, Kristian W.; Lemmon, Gordon H.; DeLuca, Samuel L.
- Biochemistry, Vol. 49, Issue 14
PyRosetta: a script-based interface for implementing molecular modeling algorithms using Rosetta
journal, January 2010
- Chaudhury, S.; Lyskov, S.; Gray, J. J.
- Bioinformatics, Vol. 26, Issue 5, p. 689-691
Computer simulation of protein folding
journal, February 1975
- Levitt, Michael; Warshel, Arieh
- Nature, Vol. 253, Issue 5494
The MARTINI Force Field: Coarse Grained Model for Biomolecular Simulations
journal, July 2007
- Marrink, Siewert J.; Risselada, H. Jelger; Yefimov, Serge
- The Journal of Physical Chemistry B, Vol. 111, Issue 27
A backbone-based theory of protein folding
journal, October 2006
- Rose, G. D.; Fleming, P. J.; Banavar, J. R.
- Proceedings of the National Academy of Sciences, Vol. 103, Issue 45
Simple data and workflow management with the signac framework
journal, April 2018
- Adorf, Carl S.; Dodd, Paul M.; Ramasubramani, Vyas
- Computational Materials Science, Vol. 146
Monte Carlo-minimization approach to the multiple-minima problem in protein folding.
journal, October 1987
- Li, Z.; Scheraga, H. A.
- Proceedings of the National Academy of Sciences, Vol. 84, Issue 19
Global Optimization by Basin-Hopping and the Lowest Energy Structures of Lennard-Jones Clusters Containing up to 110 Atoms
journal, July 1997
- Wales, David J.; Doye, Jonathan P. K.
- The Journal of Physical Chemistry A, Vol. 101, Issue 28
Clustering Molecular Dynamics Trajectories: 1. Characterizing the Performance of Different Clustering Algorithms
journal, October 2007
- Shao, Jianyin; Tanner, Stephen W.; Thompson, Nephi
- Journal of Chemical Theory and Computation, Vol. 3, Issue 6
MDTraj: A Modern Open Library for the Analysis of Molecular Dynamics Trajectories
journal, October 2015
- McGibbon, Robert T.; Beauchamp, Kyle A.; Harrigan, Matthew P.
- Biophysical Journal, Vol. 109, Issue 8
DBSCAN Revisited, Revisited: Why and How You Should (Still) Use DBSCAN
journal, August 2017
- Schubert, Erich; Sander, Jörg; Ester, Martin
- ACM Transactions on Database Systems, Vol. 42, Issue 3
Density-based cluster algorithms for the identification of core sets
journal, October 2016
- Lemke, Oliver; Keller, Bettina G.
- The Journal of Chemical Physics, Vol. 145, Issue 16
Using a Coarse-Grained Modeling Framework to Identify Oligomeric Motifs with Tunable Secondary Structure
journal, September 2021
- Walker, Christopher C.; Meek, Garrett A.; Fobe, Theodore L.
- Journal of Chemical Theory and Computation, Vol. 17, Issue 10
Identifying ligand binding sites and poses using GPU-accelerated Hamiltonian replica exchange molecular dynamics
journal, December 2013
- Wang, Kai; Chodera, John D.; Yang, Yanzhi
- Journal of Computer-Aided Molecular Design, Vol. 27, Issue 12
SPICKER: A clustering approach to identify near-native protein folds
journal, January 2004
- Zhang, Yang; Skolnick, Jeffrey
- Journal of Computational Chemistry, Vol. 25, Issue 6
SciPy 1.0: fundamental algorithms for scientific computing in Python
journal, February 2020
- Virtanen, Pauli; Gommers, Ralf; Oliphant, Travis E.
- Nature Methods
Silhouettes: A graphical aid to the interpretation and validation of cluster analysis
journal, November 1987
- Rousseeuw, Peter J.
- Journal of Computational and Applied Mathematics, Vol. 20