The chemistry of life unfolds in heterogeneous, dynamic environments where nanoscale context and weak interactions shape molecular outcomes. While traditional biochemical approaches emphasize strong and specific binding, transient and nonspecific interactions are now recognized as central to biological regulation and to the adaptive behavior of emerging bio-inspired materials. These weak interactions remain difficult to characterize, however, because their fast dynamics lie beyond the reach of many conventional methods.

Our group develops new optical microscopy methods to observe these interactions at the level of single molecules in both living cells and model systems. By pushing the bounds of current technology, we aim to transform microscopy from a tool for visualizing structures into a quantitative probe of how molecules move, interact, and collectively give rise to the functions of living systems.

Microsecond-to-millisecond single-molecule imaging

Single-molecule tracking follows individual molecules as they move and interact, revealing transient behaviors that are obscured in measurements averaged over large populations. Its temporal resolution, however, has been constrained by the frame rate of the camera, restricting tracking to comparatively slow-moving species and leaving the rapid dynamics of small molecules inaccessible.

We develop methods that overcome this limit. Our approach, SpeedyTrack, encodes temporal information into the spatial domain of the detector, enabling molecules to be tracked far faster than the camera frame rate would otherwise permit, with microsecond time resolution. We are now extending these principles to resolve motion in three dimensions and to related single-molecule schemes, including new approaches for encoding additional dimensions of information, such as single-molecule spectra and orientations. Together, we aim to explore new regimes of molecular motion and interaction that have been largely inaccessible.

Applications of single-molecule imaging

The second major thrust of our research is applying our state-of-the-art tools to understanding molecular processes. As one example, we are interested in investigating mechanisms of molecular search. The efficiency of chemical processes depends not only on binding strength but also on the rate at which molecules encounter each other. Within cells, biomolecules rely on stochastic encounters to react and perform the functions of life.

We study how small molecules and peptides search for their targets, including at the cell membrane, the target site for many therapeutic compounds. By tuning the strength and lifetime of their transient interactions, we look for general principles governing how molecules find their targets, with implications for cellular signaling and for the design of more effective therapeutics.

Super-resolution microscopy with vibrational contrast

Super-resolution fluorescence microscopy resolves structures far below the diffraction limit by localizing individual molecules one at a time. Its multiplexing capacity, however, is limited by the relatively broad spectral features of fluorescence. Raman spectroscopy offers narrow spectral features and vibrational contrast, but signals are typically too weak for nanoscale imaging. We are developing methods that use plasmonic nanoparticles to locally amplify these signals. By accumulating many such events, we aim to build super-resolution maps of protein interactions in living cells.