# Supramolecular Strategies to Modulate Biomolecular Folding and Assembly

> **NIH NIH R35** · UNIVERSITY OF ROCHESTER · 2024 · $385,000

## Abstract

PROJECT SUMMARY
Natural processes, such as protein expression, cell differentiation, and gene transcription, depend
on biomolecules to adopt specific assembly states and secondary structures, primarily
shepherded by noncovalent interactions. These noncovalent interactions also scaffold the
formation of multicomponent and three-dimensional supramolecular complexes that provide
access to architectures with (1) length scales much larger than their individual components and
(2) dynamic, reconfigurable structures enabled by the finite lifetime of the noncovalent bond.
However, traditional therapeutic and diagnostic interventions favor the use of small molecules
with fixed structures to attempt to interrupt or direct these natural processes. We hypothesize that,
to fully understand, interrogate, and modulate natural processes, synthetic constructs with specific
noncovalent interactions that operate at length scales and with dynamics commensurate with their
natural targets are needed. The overarching goal of the proposed research is to exploit the
synthetic potential of supramolecular chemistry to develop new noncovalent motifs and reactions
to interface with and intervene in biological processes. In pursuit of this goal, one research
direction is developing supramolecular mimics of natural chaperones. Protein folding is a chaotic
process that relies on natural chaperones to marshal proteins towards their functional structures.
We recently discovered a series of amphiphilic molecules that assemble into supramolecular
capsules and inhibit the fibrillation of an amyloid beta protein fragment. Future work in this area
seeks to capitalize on this discovery to establish structure-function relationships that relate
molecular structure, assembly properties, and chaperone-like function, and establish dynamic
photoswitches to modulate the hydrophobicity of our supramolecular chaperones in situ and
induce protein refolding. Our second research direction will establish new recognition motifs for
canonical (Watson-Crick-Franklin, WCF) and non-canonical base pairs in nucleic acids. Though
most base-base interactions in DNA and RNA consist of WCF interactions, non-WCF interactions
and mismatched base pairs are important structural features, implicated in DNA cytotoxicity and
RNA function. Typical approaches to target such structures rely on small molecule intercalators
that require identifiable binding pockets. To circumvent this limitation, we are developing bifacial
nucleobases that harness inherent base-pairing to target specific nucleic acid sequences and
structural folds. In sum, the proposed research program will advance fundamental understanding
about the molecular recognition of biomolecular primary and secondary structures and establish
new recognition motifs that will underpin the development of future diagnostics and therapeutics.

## Key facts

- **NIH application ID:** 10941034
- **Project number:** 1R35GM155222-01
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Benjamin Edward Partridge
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $385,000
- **Award type:** 1
- **Project period:** 2024-08-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10941034

## Citation

> US National Institutes of Health, RePORTER application 10941034, Supramolecular Strategies to Modulate Biomolecular Folding and Assembly (1R35GM155222-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10941034. Licensed CC0.

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