Synthetic and Computational Design Insights toward Mimicking Protein Binding of Phosphate

Whitney C. Fowler, Chuting Deng, O. Therese Teodoro, Juan J. de Pablo, Matthew V. Tirrell

Research output: Contribution to journalArticlepeer-review


The unique and precise capabilities of proteins are renowned for their specificity and range of application. Effective mimicking of protein-binding offers enticing potential to direct their abilities toward useful applications, but it is nevertheless quite difficult to realize this characteristic of protein behavior in a synthetic material. Here, we design, synthesize, and evaluate experimentally and computationally a series of multicomponent phosphate-binding peptide amphiphile micelles to derive design insights into how protein binding behavior translates to synthetic materials. By inserting the Walker A P-loop binding motif into this peptide synthetic material, we successfully implemented the protein-binding design parameters of hydrogen-bonding and electrostatic interaction to bind phosphate completely and selectively in this highly tunable synthetic platform. Moreover, in this densely arrayed peptide environment, we use molecular dynamics simulations to identify an intriguing mechanistic shift of binding that is inaccessible in traditional proteins, introducing two corresponding new design elements─flexibility and minimization of the loss of entropy due to ion binding, in protein-analogous synthetic materials. We then translate these new design factors to de novo peptide sequences that bind phosphate independent of protein-extracted sequence or conformation. Overall, this work reveals that traditional complex conformational restrictions of binding by proteins can be replaced and repurposed in a multicomponent peptide amphiphile synthetic material, opening up opportunities for future enhanced protein-inspired design.

Original languageEnglish (US)
Pages (from-to)300-311
Number of pages12
JournalBioconjugate Chemistry
Issue number3
StatePublished - Mar 20 2024
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2024 The Authors. Published by American Chemical Society

PubMed: MeSH publication types

  • Journal Article


Dive into the research topics of 'Synthetic and Computational Design Insights toward Mimicking Protein Binding of Phosphate'. Together they form a unique fingerprint.

Cite this