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NIH grant 1R35GM162238-01: Optical microcavities for label-free single-molecule analysis of biomolecules
Institute: {'code': 'GM', 'abbreviation': 'NIGMS', 'name': 'National Institute of General Medical Sciences', 'admin_org_id': '12500024', 'admin_funding_url': ''}. PI: Randall H Goldsmith. Award: $2196715.
Start: 2026-09-19T00:00:00.
Optical Microcavities for Label-Free Single-Molecule Analysis of Biomolecules
Solution-phase conformation of biomolecules is at the heart of a major fraction of molecular biology, affecting
everything from enzymology to cell signaling to genetic information transfer. Consequently, tools to characterize
biomolecule conformation, or how that conformation changes, are central to spurring future insights on biolog-
ical mechanism and disease etiology. This MIRA builds on a breakthrough recently reported by our group in
Nature, whereby individual molecules are detected in a manner that 1) is completely label free, 2) offers signal-
to-noise ratios >100, 3) is solution-phase (ie, the measurement is performed >1μm away from a solid surface),
and 4) most importantly, allows hydrodynamic profiling of each molecule by determination of diffusion times.
The technology takes advantage of the enhanced light-matter interaction provided by fiber-based Fabry-Pérot
optical microcavities (FFPCs). The combination of points 3) and 4) above is critical, as surfaces can be highly
perturbing to biomolecule conformation. We are eager to leverage this exciting new method to create an impact-
ful new tool for examining conformations of biomolecules of biomedical significance.
There is an outstanding need for a method that can identify a solution-phase conformational change, that is
quantitative, high resolution, fast, label-free, benchtop, requires only simple analysis, and requires only minimal
sample volume and concentration. While NMR, analytical ultracentrifugation, capillary electrophoresis, dy-
namic light scattering (DLS), fluorescence correlation spectroscopy (FCS), mass spectrometry with ion mobility,
and mass photometry can satisfy some of these requirements, there is no current technique that can satisfy all of
these requirements. Our new microcavity-based method can satisfy these constraints and provide a way to de-
termine the diffusion constant (D), and through D, the hydrodynamic radius (Rh). By satisfying the constraints
above, the method has the potential to be a disruptive addition to any research effort or biotechnology pipeline
where there is need to quickly and conveniently demonstrate that a conformational change has occurred.
More broadly, this MIRA will drive a program whereby photonic structures are deployed to develop new forms
of label-free single-molecule spectroscopy, contributing to an ongoing technological revolution bringing power-
ful new ways to observe biomolecular structure and dynamics.document fetched 2026-09-27 02:45