# Interferometric Plasmon Ruler for Elucidating Structural Dynamics on the SingleMolecule Level

> **NIH NIH R21** · BOSTON UNIVERSITY (CHARLES RIVER CAMPUS) · 2022 · $229,758

## Abstract

Summary
The structure of important biomolecules is intrinsically dynamic, and there is an important need for optical tools
that can probe the structural dynamics of biopolymers at the single molecule level with high temporal resolution
and without limitation in maximum observation time. Dynamic molecular rulers, such as Fluorescence
Resonance Energy Transfer (FRET) dye pairs or plasmon rulers (PRs), as well as tethered particle assays are
currently available optical methods to probe the structural dynamics of individual molecules. FRET is, however,
plagued by the limited photophysical stability of conventional organic dyes that serve as energy donor and
acceptor. Photobleaching limits the maximum number of photoexcitation and emission cycles and, thus, defines
fundamental limitations for a continuous monitoring of molecular structure. Conventional PRs and tethered
particle assays can provide high signal intensities without blinking or limitation in observation time. The caveat
of these approaches is, however, the large size of the particles with typical dimensions on the order of tens of
nanometers or larger. This proposal develops a new class of PRs that is based on the phenomenon that the
distance-dependent coupling of a gold nanoparticle (NP) tethered to a gold film through a biopolymer modulates
the interferometric scattering signal of the NP. This new PR is based on an interferometric detection of plasmon
coupling and allows the use of NPs with dimensions as small as 5 nm as probes. The interferometric PRs will
make it possible to monitor the structural dynamics of individual biopolymers with high temporal resolution and
with no need to compromise between temporal resolution and the duration of the observation. The work
described in this proposal will implement interferometric PRs using DNA as biopolymer and characterize their
performance. After validating the interferometric PR concept with DNA, the interferometric PR platform will be
expanded to allow the characterization of the structural dynamics of the intrinsically disordered tau protein in the
presence of a lipid membrane of defined composition. The ability of the interferometric PR to monitor the
structural dynamics of a single tau molecule and to detect membrane-induced changes in the structure and
dynamics of the biopolymer will be tested. The research described in this proposal will result in a new dynamic
molecular ruler technology that overcomes longstanding limitations of conventional optical molecular rulers in
terms of the size and photophysical stability of the probes. The specific Aims of this proposal are to:
Aim1: Implement the Interferometric PR and Test Its Applicability to Characterize Structural Fluctuations in
Single DNA Molecules
Aim2: Implement and Validate an Interferometric PR for Probing the Structural Dynamics of a Single Tau
Protein in the Vicinity of a Membrane

## Key facts

- **NIH application ID:** 10450310
- **Project number:** 1R21GM143672-01A1
- **Recipient organization:** BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
- **Principal Investigator:** Bjoern Markus Reinhard
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $229,758
- **Award type:** 1
- **Project period:** 2022-09-20 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10450310

## Citation

> US National Institutes of Health, RePORTER application 10450310, Interferometric Plasmon Ruler for Elucidating Structural Dynamics on the SingleMolecule Level (1R21GM143672-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10450310. Licensed CC0.

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