Interdisciplinary PhD in Structural and Computational Biology and Quantitative Biosciences

Randall H. Goldsmith

Associate Professor, Department of Chemistry Lab Website 263-8315

3309A Chemistry
1101 University Ave
Madison, WI 53706-1322


B.A., Cornell University
Ph.D., Northwestern University
Postdoctoral, Stanford University

Single-molecule methods to study chemical reactions, biophysical processes, and materials properties

Optical Microresonators as Single-Molecule Spectrometers

Single-particle spectroscopy is a powerful tool for the investigation of the properties of nanomaterials because unsynchronized processes can be directly observed. However, the traditional reliance upon photoluminescence for single-particle measurements limits such investigations to systems where the target particle or molecule is emissive.

Microresonators with ultrahigh Quality (Q) Factor have amazing optical properties.  These resonators can demonstrate line widths down to tens of femtometers, making them tremendously sensitive to their microenvironment.

Ultrahigh-Q optical microresonators offer a way of eliminating the need for emission by enabling additional sensitive means of interaction with individual particles. We have developed a microresonator spectrometer to perform spectroscopy on individual particles and molecules. Using a sophisticated double-modulation scheme, our microresonator spectrometer can detect resonance shifts down to a single attometer!

We are deploying our microresonator spectrometer in a number of exciting areas.

In collaboration with Professor David Masiello’s theoretical chemistry group at University of Washington, we are exploring hybrid photonic-plasmonic systems that exhibit strange looking lineshapes called Fano resonances!  Such lines tell us about all of the ingredients of the interaction, including coupling strength and dephasing.

Conductive polymers are materials of tremendous technological importance, but no one has been able to prove their electronic structure at the single-polymer level because they are non-emissive!  We have recently taken the first single conductive polymer absorption spectrum and are using our new spectrometer to unravel the interplay between crystallinity and electronic structure. In this capacity, we are collaborating with Professor Alan Aspuru-Guzik’s theoretical chemistry group at Harvard University and Professor John Wright’s group at UW.

We are also pushing our microresonator spectrometer to new limits of sensitivity in order to probe the time-varying electronic structure of working metaloenzymes. Our dream experiment is to take a molecule movie of a single biocatalyst in action!  We are collaborating with Professor Thomas Brunold at UW.


Watching individual homogeneous catalysts in action

Homogeneous catalysis relies on an intricate series of bond breaking, electron transfer, and bond forming reactions. Production of more active, selective, and easily recyclable (ie., “greener”) catalysts is necessary for the availability of next generation drugs, fuels, and materials. Mechanistic study informs the design of better catalysts, and single-molecule spectroscopy is a powerful tool for mechanistic study because it allows unsynchronized or rare processes to be directly observed. We are looking for dynamic and static heterogeneity in the catalyst population, behavior that has been previously seen in enzymes. Organometallic catalysts cycle through states of variable activity and selectivity, likely due to a changing coordination environment. These changes are unsynchronized across the catalyst population and many cannot be observed in ensemble-averaged experiments. We will search for this heterogeneity, quantify transition kinetics, and vary ligand and substrate properties to establish structure-behavior relationships. The goal is to build a detailed understanding of the microscopic events in homogeneous catalysis through revolutionary new observations of individual catalysts in operation. We will observe reaction intermediates that have so far been only speculated upon or indirectly inferred and quantify the lifetimes of those intermediates in active catalysts, not analogs. We are using single-molecule fluorescence microscopy to perform these measurements, and experiments frequently involve combinations of microscopy, molecular design, synthesis, and nanophotonics.

We have recently measured the initiation dynamics of individual molecular palladium complexes and shown that we could model their highly heterogeneous behavior.  We have also explored energy transfer between dendrimeric catalysts and the kinetics of surface anchor degradation.  New surface attachment chemistries are being actively developed.



Single-Molecule Biophysics

Because single-molecule measurements allow examination of unsynchronized dynamics, they provide unique mechanistic details about biological molecules.  We are blending advanced photonic and microfluidic technologies to allow increasingly potent new single-molecule measurements.

In one project, we are studying solution-phase conformations of intrinsically disordered proteins involved in Alzheimer’s Disease.  Critical to this approach is avoiding surface-attachment, a common single-molecule technique, as this practice has been shown to alter protein folding dynamics and may dominate the crowding effect. We can avoid this difficulty, while still observing the molecule for long enough times to capture full folding trajectories, with a specialized microfluidic device that uses electroosmotic flows to cancel Brownian motion of single fluorescent molecules in solution. We have recently used this device to observe single solution-phase proteins for many seconds without immobilization. Our trajectories will provide unique information about how solution-phase behavior, improving the picture of in vivo function, signaling, and pathological misfolding. We are collaborating in this endeavor with Professor Martin Margittai at the University of Denver.

In a second project, we are using nanophotonic devices called Zero-Mode Waveguides to enable single-molecule measurements in increasingly concentrated and complex environments.  We have recently used a combination of ZMW’s and Forster Resonance Energy Transfer (FRET) to carry out single-molecule experiments at the highest concentrations ever performed, up to 1mM!  We have deployed these techniques to understand regulation mechanisms in cyclic nucleotide binding domains that control pace-making ion channels.  We are collaborating with Professor Baron Chanda at UW Neuroscience.

Areas of Expertise

  • Biophysical Chemistry
  • Biotechnology
  • Protein Folding Design & Function
  • Single Molecule Biophysics
  • Spectroscopy Microscopy Imaging