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Apparatus and Instrumentation for Single Molecule Spectroscopy



  • Rational drug design: relating the static structure and dynamic function of biomolecules
  • Single molecule DNA sequencing
  • Rational de novo design and directed evolution of enzymes
  • Nanoscale biosensing
  • Design, control, and improvement of basic industrial processes


  • Continuous laser source is more economical and user friendly than pulsed sources
  • Registers photon arrival times
  • High resolution
  • Allows research parameter expansion
  • Prevents data overload
  • Enables greater understanding of continuous molecular behaviour as well as reactive mechanisms like drug binding


Haw Yang and Lucas Watkins at Berkeley Lab have developed instrumentation and algorithms that expand and enhance the capabilities of single molecule spectroscopy.  The new inventions make strides towards establishing a quantitative relationship between the static structure and the dynamic function of biomolecules – a key relationship that needs to be better understood if rational drug design is to make significant advances.  The Berkeley Lab inventions could also be applied to the use of single molecule spectroscopy for nanoscale biosensing, single molecule DNA sequencing, and the rational de novo design and directed evolution of enzymes.  The mechanistic understanding of chemical reactivity that can be provided by high-resolution single molecule spectroscopy is essential for the design, control, and improvement of many basic industrial processes as well.

Berkeley Lab’s apparatus consists of an inverted microscope system that uses an economical and user-friendly continuous laser source while retaining many of the advantages of pulsed sources, including the ability to register photon arrival times.  This fluorescence-based detection system yields more valuable information than those that rely on arbitrary data binning and adds modular, server-based detection elements, ensuring that huge amounts of data won’t overload the system and that research parameters can be expanded easily. (Reference number IB-2010)

Both of the Berkeley Lab algorithms can be used in conjunction with the new Berkeley Lab apparatus or as stand-alone programs analyzing data acquired using existing instrumentation.  Both are based on the detection of individual photons that have interacted with an immobilized molecule and are not limited to flourescence-tagged molecules. One algorithm is applicable to molecular behavior that is continuous. (Reference number IB-2009)  The second algorithm analyzes rapid molecular movements that are often critical to understanding reactive mechanisms such as drug binding, but that are most often lost in typical data binning and thresholding methods. (Reference number IB-2098)

The Berkeley Lab researchers have also have invented a noninvasive technique for 3-D tracking of a single moving particle or molecule while providing concurrent spectroscopic readouts. The method employs a confocal setup to form an intensity gradient for Z-axis resolution. The researchers have demonstrated nanometer spatial resolution with submillisecond response time using near-infrared light scattering to track a gold nanoparticle. (Reference number IB-2079)


  • IB-2009, 2010: Patents pending. Available for licensing or collaborative research
  • IB-2098: Available for licensing or collaborative research
  • IB-2079: Published PCT Patent Application. Available for licensing or collaborative research.


Watkins, L. P., Yang, H., "Information Bounds and Optimal Analysis of Dynamic Single Molecule Measurements," Biophysical Journal 2004, 86, 4015-4029.

Watkins, L.P., Yang, H., "Detection of Intensity Change Points in Time-Resolved Single Molecule Measurements," J. Phys. Chem. 2005, 109, 617-628.

IB: 2079:
Cang, H., Rizvi, A.H., Wong, C.M., Yang, H., Su, Shan. "Confocal Three-Dimensional Tracking of a Single Nanoparticle with Concurrent Spectroscipic Readouts." Applied Physics Letter. 88, 223901. 2006

REFERENCE NUMBER: IB-2009, IB-2010, IB-2098, IB-2079

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