Combining simulations and experiments for the molecular engineering of multifunctional collagen mimetic peptide-based materials

Amber M. Hilderbrand, Phillip A. Taylor, Francesca Stanzione, Mark LaRue, Chen Guo, Arthi Jayaraman, April M. Kloxin

Research output: Contribution to journalArticlepeer-review


Assembling peptides allow the creation of structurally complex materials, where amino acid selection influences resulting properties. We present a synergistic approach of experiments and simulations for examining the influence of natural and non-natural amino acid substitutionsviaincorporation of charged residues and a reactive handle on the thermal stability and assembly of multifunctional collagen mimetic peptides (CMPs). Experimentally, we observed inclusion of charged residues significantly decreased the melting temperature of CMP triple helices with further destabilization upon inclusion of the reactive handle. Atomistic simulations of a single CMP triple helix in explicit water showed increased residue-level and helical structural fluctuations caused by the inclusion of the reactive handle; however, these atomistic simulations cannot be used to predict changes in CMP melting transition. Coarse-grained (CG) simulations of CMPs at experimentally relevant solution conditions, showed, qualitatively, the same trends as experiments in CMP melting transition temperature with CMP design. These simulations show that when charged residues are included electrostatic repulsions significantly destabilize the CMP triple helix and that an additional inclusion of a reactive handle does not significantly change the melting transition. Based on findings from both experiments and simulations, the sequence design was refined for increased CMP triple helix thermal stability, and the reactive handle was utilized for the incorporation of the assembled CMPs within covalently crosslinked hydrogels. Overall, a unique approach was established for predicting stability of CMP triple helices for various sequences prior to synthesis, providing molecular insights for sequence design towards the creation of bulk nanostructured soft biomaterials.

Original languageEnglish (US)
Pages (from-to)1985-1998
Number of pages14
JournalSoft Matter
Issue number7
StatePublished - Feb 21 2021
Externally publishedYes

Bibliographical note

Funding Information:
The computational work in this paper and the ongoing work on coarse grained CMP model dissemination via were financially supported by National Science Foundation (NSF) Grants 1703402 and 1835613, respectively. The computational work in this paper was also supported by the information technologies resources at the University of Delaware, specifically in the form of the Farber high-performance computing resources. The experimental work in this paper was supported in part by grants on related work from the National Science Foundation DMR BMAT (1253906), the Pew Charitable Trusts (26178), and National Institutes of Health (NIH) Director’s New Innovator Award (DP2 HL152424-01). The authors would like to acknowledge the University of Delaware Mass Spectrometry Core facilities, supported by the Delaware COBRE programs with grants from the National Institute of General Medical Sciences (NIGMS) (P20GM104316 and P30GM110758) from the NIH, and the Millicent Sullivan group for use of equipment. The authors would like to thank Dr. Bryan Sutherland for helpful feedback and discussions on drafts of this manuscript.

Publisher Copyright:
© The Royal Society of Chemistry 2021.

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