Weiss, Shimon

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Distinguished Professor
Dean M. Willard Chair
Department of Chemistry and Biochemisty
Department of Physiology
Bar-llan University Ramat-Gan
Department of Physics
Structural Biology
California NanoSystems Institute. ACCESS Program - Dept. of Molecular, Cell & Integrative Physiology

Contact Information

Young Hall 2037A
(310) 794-0093
Young Hall 2002 & 2041
(310) 794-6685

Short Biography

Shimon received his PhD in Electrical Engineering from the Technion, Israel in 1989. After a year of postdoctoral research in AT&T Bell Laboratories, he was hired by Lawrence Berkeley National Laboratory as a staff Scientist. In 2001 he joined the departments of Chemistry & Biochemistry and Physiology at UCLA

Research Interest

Identifying and cataloging all gene sequences and their corresponding protein high-resolution static 3-dimensional structures is only a prelude to the real challenges of future biological inquiries. We need to understand the dynamic structural changes of isolated macromolecules undergoing biochemical reactions. We need to identify transient interactions between macromolecules. We need to decipher the cell circuitry and its detailed time-dependent responses to various stimuli. We need to decode intracellular and extracellular communication signals and the corresponding molecular-level responses of live cells, tissues and whole organs. Analytical tools will need to be developed in order to identify and measure these molecular conformations and interactions. High-sensitivity fluorescence methods will play a vital role in this endeavor because they offer many advantages for probing isolated molecules and molecules in live cells, tissues and organs. Fluorescence is non-invasive; it provides imaging and sectioning capabilities in three dimensions; it has high sensitivity, down to the single molecule level, and it allows the observation of molecular- and organelle-specific signals. Our group develops and applies ultrahigh-resolution, ultrahigh-sensitivity fluorescence imaging and spectroscopy tools to solving outstanding problems in biology.

Conformational dynamics of biomolecules: Many of the molecular machines that are essential for cell function and survival (transcription, replication, translation, recombination, splicing, protein folding etc.) are asynchronous, have multiple kinetic pathways and intermediates, and are comprised of several interacting components. The ability to watch one molecule at a time helps us obtain unique information on distribution functions of relevant observables, resolve subpopulations in heterogeneous samples, and record asynchronous time trajectories of observables that would otherwise be hidden. For example, dynamic distance changes between two sites on a macromolecule (or between two different molecules) can be measured via single-pair fluorescence resonance energy transfer (spFRET) by following spectral changes in the emission of a single donor-acceptor pair. Orientational changes can be detected via single-molecule fluorescence polarization anisotropy (smFPA) by following changes in the dipole orientation of a rigidly-attached or tethered probe. Our group developed such tools and uses them to study protein folding and transcription on the single-molecule level. We study the folding reaction energy landscape, pathways, conformational distributions and folding intermediates. The same tools are used to answer 25-years-old outstanding questions about the mechanisms of DNA transcription by the enzyme RNA polymerase. We are studying the relative motions between the enzyme and its DNA molecular track, the conformational motions in the enzyme itself, and conformational transitions in the DNA during the various steps of the transcription reaction.

Development of semiconductor nanocrystals as biological probes: Single-molecule experiments are currently performed predominantly in in-vitro environments. The ultimate challenge is to image cellular substructures, determine the relationships and dynamics of vesicles and organelles, describe existing conformational dynamics and biomolecular interactions, and localization all of the above in-vivo with single molecule sensitivity and nanometer-accuracy. This will allow the study of enzymes and multi-component molecular machines in their natural environment, with the signaling and regulation circuitry all wired-up. Towards the accomplishment of this tremendously complex task, we are developing colloidal fluorescent semiconductor nanocrystals (a class of quantum dots) for biological labeling. Nanocrystals posses several properties that make them very attractive as fluorescent probes for in-vivo single-molecule experiments: broad excitation spectra, narrow emission spectra, precise-tunable emission peaks, long fluorescence lifetimes, and negligible photobleaching. We are developing organic coatings, bioconjugation schemes, targeting strategies, and unique instrumentation that take advantage of nanocrystals spectral properties. Recently, we have shown how these distinctive properties increase the resolution of fluorescence microscopy measurements down to the nanometer level using far-field optics. We have also shown that their long fluorescence lifetime can be used to observe molecules and organelles in live cells without interference from autofluorescence background (a pre-requisite for single molecule detectability). We are currently pursuing applications in genomics (physical mapping, genome rearrangement), vesicle trafficking, cargo selection and in-vivo motility assays of molecular motors.

Biomolecular interactions by coincidence detection: Understanding the intricate network of protein interactions that take place within the cell of an organism allows the understanding of the mechanisms that control its growth, maintenance, and disease. Protein-protein interactions are most commonly identified using the yeast two-hybrid (Y2H) assay. However, Y2H has several limitations including complications associated with the use of protein fusions, incorrect protein folding, incorrect post-translational modification, potential for toxicity and incompatibility with DNA binding proteins. We are developing a new method for detecting static and transient macromolecular interactions with ultrahigh sensitivity, based on two-color coincident detection of single molecules in a confocal detection volume. Towards this end, we are developing unique fluorescent reagents, site-directed labeling schemes and novel single-molecule detection and analysis tools for monitoring protein-protein and protein-DNA interactions initially in-vitro and at a later stage in-vivo. We envision applications in cellular signaling and bio-sensing.




Honors & Awards

  • Rothschild Fellowship Rothschild Fellowship
  • Royal College of Physicians, London Rank Prize
  • Michael and Kate Barany Biophysical Society Award
  • Optical Society of America Fellow
  • The Director Outstanding Performance Award, Lawrence Berkeley Laboratory
  • AAAS
  • ACS
  • APS
  • Biophysical Society
  • Fellow, Optical Society of America (1999)


Ebenstein, Y. Gassman, N. Kim, S. Weiss, S.   Combining atomic force and fluorescence microscopy for analysis of quantum-dot labeled protein-DNA complexes J Mol Recognit, 2009; 22(5): 397-402.
Pinaud, F. Michalet, X. Iyer, G. Margeat, E. Moore, H. P. Weiss, S.   Dynamic Partitioning of a Glycosyl-Phosphatidylinositol-Anchored Protein in Glycosphingolipid-Rich Microdomains Imaged by Single-Quantum Dot Tracking Traffic, 2009; 10(6): 691-712.
Gassman, N. R. Ho, S. O. Korlann, Y. Chiang, J. Wu, Y. Perry, L. J. Kim, Y. Weiss, S.   In vivo assembly and single-molecule characterization of the transcription machinery from Shewanella oneidensis MR-1 Protein Expr Purif, 2009; 65(1): 66-76.
Ebenstein, Y. Gassman, N. Kim, S. Antelman, J. Kim, Y. Ho, S. Samuel, R. Michalet, X. Weiss, S.   Lighting up individual DNA binding proteins with quantum dots Nano Lett, 2009; 9(4): 1598-603.
Antelman, J. Wilking-Chang, C. Weiss, S. Michalet, X.   Nanometer distance measurements between multicolor quantum dots Nano Lett, 2009; 9(5): 2199-205.
Bentolila, L. A. Ebenstein, Y. Weiss, S.   Quantum dots for in vivo small-animal imaging J Nucl Med, 2009; 50(4): 493-6.
Kim, Y. Ho, S. O. Gassman, N. R. Korlann, Y. Landorf, E. V. Collart, F. R. Weiss, S.   Efficient site-specific labeling of proteins via cysteines Bioconjug Chem, 2008; 19(3): 786-91.
Iyer, G. Michalet, X. Chang, Y. P. Pinaud, F. F. Matyas, S. E. Payne, G. Weiss, S.   High affinity scFv-hapten pair as a tool for quantum dot labeling and tracking of single proteins in live cells Nano Lett, 2008; 8(12): 4618-23.
Korlann, Y. Dertinger, T. Michalet, X. Weiss, S. Enderlein, J.   Measuring diffusion with polarization-modulation dual-focus fluorescence correlation spectroscopy Opt Express, 2008; 16(19): 14609-16.
Hamadani, K. M. Weiss, S.   Nonequilibrium single molecule protein folding in a coaxial mixer Biophys J, 2008; 95(1): 352-65.
Schipper, M.L.; Iyer, G.; Koh, A.L.; Cheng, Z.; Ebenstein, Y.; Aharoni, A.; Keren, S.; Bentolila, L.A.; Li, J.; Rao, J.; Chen, X.; Banin, U.; Wu, A.M.; Sinclair, R.; Weiss, S.; Gambhir, S.S.   Particle Size, Surface Coating, and Pegylation Influence the Biodistribution of Quantum Dots in Living Mice Small, 2008; 5(1): 126-34.
Bentolila, L.A.; Michalet, X.; and Weiss, S   Quantum Optics: Colloidal Fluorescent Semiconductor Nanocrystals (Quantum dots) in Single-Molecule Detection and Imaging Springer Series in Biophysics: Single Molecules and Nanotechnology, 2008; 12(Edited by Rudolf Rigler and Horst Vogel): 53-81.
Kapanidis, A.N.; Weiss, S   Single-molecule FRET analysis of the path from transcription initiation to elongation RNA Polymerases as Molecular Motors, 2009; Buc, H.; Strick, T.; Eds., : 115-156.
Chang, Y. P.; Pinaud, F.; Antelman, J.; Weiss, S.   Tracking bio-molecules in live cells using quantum dots J Biophotonics, 2008; 1(4): 287-98.
Nir, E.; Jäger, M.; and Weiss, S   Alternating Laser Excitation Spectroscopy of freely diffusing single molecules: Application to biomolecular structure, dynamics and interactions Handai Nanophotonics, 2007; 3(Masuhara, H.; Kawata, S.; and Tokunaga, F. Eds.): 23-42.
Kapanidis, A.N.; Heilemann, M.; Margeat, E.; Kong, X.; Nir, E.; Weiss, S.   Alternating-Laser Excitation of Single Molecules Single-Molecule Techniques: A Laboratory Manual, 2007; Selvin, P.; Ha, T.; Eds.(Chapter 6): .
Michalet, X.; Siegmund, O.H.W.,; Vallerga, J.V.; Jelinsky, P.; Millaud, J.E.; Arisaka, K.; Weiss, S.   Detectors for Microscopy: Next-generation 3-D detector improves single-molecule imaging Laser Focus World, 2007; 43: 97-101.
Schipper, M.L.; Cheng, Z.; Lee, S.W.; Keren, S.; Bentolila, L.A.; Sundaresan, G.; Iyer, G.; Gheysens,O.; Ebenstein, Y.; Li, J.; Rao, J.; Chen, X.; Wu, A.M.; Weiss, S.; Gambhir, S.S.   MicroPET-Based Biodistribution of Quantum Dots in Living Mice J. of Nuclear Medicine, 2007; 48(9): 1511-8.
Doose, S.; Heilemann, M.; Michalet, X.; Weiss, S.; and Kapanidis A.N.   Periodic Acceptor Excitation Spectroscopy of Single Molecules European Biophysical J., 2007; 36(6): 669-74.
Kong, X. Nir, E. Hamadani, K. Weiss, S.   Photobleaching pathways in single-molecule FRET experiments J Am Chem Soc, 2007; 129(15): 4643-54.
Laurence, T.A.; Michalet, X.; Jäger, M.; and Weiss, S.   Protein Dynamics and Interactions Single Molecule Dynamics, 2007; Yanagida, T.; Ishii, Y. Eds., : .
Majumdar, D.S.; Smirnova, I.; Kasho, V.; Nir, E.; Kong, X.; Weiss, S.; Kaback, H.R.   Single-molecule FRET Reveals a Sugar-Induced Conformational Dynamics in LacY Proc Natl Acad Sci USA, 2007; 104(31): 12640-12645.
Tsay, J.M.; Trzoss, M.; Shi, L.; Komg, X.; Selke, M.; Jung, M.E.; Weiss, S.   Singlet Oxygen Production by Peptide-coated Quantum Dot-Photosensitizer Conjugates J. Am. Chem. Soc., 2007; 129(21): 6865-6871.
Iyer, G. Pinaud, F. Tsay, J. Weiss, S.   Solubilization of quantum dots with a recombinant peptide from Escherichia coli Small, 2007; 3(5): 793-8.
Lee, N.K.; Kapanidis, A.N.; Koh, H.R.; Korlann, Y.; Ho, S.O.; Kim; Y.;Gassman, N.; Kim, S.K.; and Weiss, S.   Three-color alternating-laser excitation of single molecules: simultaneous monitoring of multiple interactions and distances Biophysical Journal, 2007; 92(1): 303-12.
Michalet, X.; Siegmund, O.H.W.; Vallerga, J.V.; Jelinsky, P.; Millaud, J.E.;Weiss,S   A space and time ?resolved single-photon counting detector for fluorescence microscopy and spectroscopy Proceedings of SPIE, 2006, 2006; 6092M: .
Pinaud, F. Michalet, X. Bentolila, L. A. Tsay, J. M. Doose, S. Li, J. J. Iyer, G. Weiss, S.   Advances in fluorescence imaging with quantum dot bio-probes Biomaterials, 2006; 27(9): 1679-87.
Bentolila LA, Weiss S   Single-step multicolor fluorescence In situ hybridization using semiconductor quantum dot-DNA conjugates Cell Biochemistry and Biophysics, 2006; 45((1) Editor-in-Chief: Edward J. Massaro): 59-70.
Margeat, E. Kapanidis, A. N. Tinnefeld, P. Wang, Y. Mukhopadhyay, J. Ebright, R. H. Weiss, S.   Direct observation of abortive initiation and promoter escape within single immobilized transcription complexes Biophys J, 2006; 90(4): 1419-31.
Michalet, X.; Siegmund, O.H.W.; Vallerga, J.V.; Jelinsky, P.; Pinaud, F.; Millaud, J.E.; Weiss, S.   Fluorescence lifetime microscopy with a time- and space-resolved single-photon counting detector Proceedings of the SPIE, 2006; 6372(63720E): .
Kapanidis, A. N.; Margeat, E.; Ho, S. O.; Kortkhonjia, E.; Weiss, S.; Ebright, R. H.   Initial transcription by RNA polymerase proceeds through a DNA-scrunching mechanism Science, 2006; 314(5802): 1144-7.
Iyer, G.; Li, J.J.; Pinaud, F.; Tsay, J.M.; Bentolila, L.A.; Michalet, X.; Weiss, S.   Near-infrared peptide-coated quantum dots for small animal imaging Proceedings of the SPIE, 2006; 6096(6096B): .
Iyer, G. Pinaud, F. Tsay, J. Li, J. J. Bentolila, L. A. Michalet, X. Weiss, S.   Peptide coated quantum dots for biological applications IEEE Trans Nanobioscience, 2006; 5(4): 231-8.
Michalet X, Siegmund OHW, Vallerga JV, Jelinsky P, Millaud JE, Weiss S   Photon-Counting H33D Detector for Biological Fluorescence Imaging Nuclear Instruments and Methods in Physics Research, 2006; 567(1): 133.
Nir, E. Michalet, X. Hamadani, K. M. Laurence, T. A. Neuhauser, D. Kovchegov, Y. Weiss, S.   Shot-noise limited single-molecule FRET histograms: comparison between theory and experiments J Phys Chem B, 2006; 110(44): 22103-24.
Michalet, X. Weiss, S. Jager, M.   Single-molecule fluorescence studies of protein folding and conformational dynamics Chem Rev, 2006; 106(5): 1785-813.
Bentolila, L. A. Weiss, S.   Single-step multicolor fluorescence in situ hybridization using semiconductor quantum dot-DNA conjugates Cell Biochem Biophys, 2006; 45(1): 59-70.
Michalet, X. Weiss, S.   Using photon statistics to boost microscopy resolution Proc Natl Acad Sci U S A, 2006; 103(13): 4797-8.
Lee, N. K. Kapanidis, A. N. Wang, Y. Michalet, X. Mukhopadhyay, J. Ebright, R. H. Weiss, S.   Accurate FRET measurements within single diffusing biomolecules using alternating-laser excitation Biophys J, 2005; 88(4): 2939-53.
Kapanidis AN, Laurence TA, Lee NK, Margeat E, Kong X, Weiss S   Alternating-laser excitation of single molecules Accounts of chemical research, 2005; 38(7): 523-33.
Siegmund, O.H.W.; Michalet, X.; Vallerga, J.V.; Jelinsky, P.; Weiss, S.   Cross Delay Line Detectors for High Time Resolution Astronomical Polarimetry and Biological Fluorescence Imaging IEEE Nuclear Science Symposium Conference Record, 2005; N14(55): 448-452.