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Zhongyu Yang

Bridging Analytical Chemistry with Protein Science, Drug Delivery/Design, and Biomaterials.

Molecular recognition and biomacromolecular interaction play important roles in protein function, drug delivery and drug function, and biomaterials chemistry. Research in our group is focused on developing new analytical methods which can detect molecular recognition/interaction, in order to understand the working mechanisms of biological systems and to guide novel materials and drug design. Our toolbox is centered on Electron Paramagnetic Resonance (EPR) spectroscopy. Other analytical techniques will also be involved in our work.

1. Molecular device and method development to rapidly detect molecular interaction.

Molecular interaction of proteins, DNAs, or lipids with ligands or drugs is essential in many biological and pharmaceutical processes. Detection of such interaction, however, is a nontrivial task mainly due to the complexity of the target systems. Of particular interest are two processes: the interaction of ligands/drugs with lipid membranes, and interaction with proteins and DNAs. While the former is related to ligand/drug delivery and diffusion within and across cellular membranes (Fig. 1A), the latter is essential in understanding the drugability of proteins or DNAs and drug mechanisms (Fig. 1B). In addition, in order to assist in drug design, rapid detection of molecular interaction is critically required, so that multiple drugs can be screened with minimal time and effort (Fig. 1C). We will therefore develop new EPR methods and molecular devices to rapidly screen various molecular interactions.

Figure 1

Figure 1. (A) Small molecule diffusion in membranes can be determined using EPR and spin labeled lipid. (B) Local dynamics and global structural changes in proteins upon interaction with ligands/drugs can be monitored using EPR. (C) An EPR-based molecular device to rapidly perform diffusion and structure/dynamics measurements.

2. Application of developed methods.

There are two biological systems on our radar in order to apply the developed methods. First, we will investigate how drugs, especially metallodrugs based on V, Cr, and Ru ion complexes, diffuse within and across cellular membranes and interact with relevant proteins and DNAs. In vivo studies have shown these metallodrugs to be promising alternatives in treating cancer and diabetes. However, how these intrinsically toxic metals help treat cancer and diabetes is a long-lasting mystery, indicating a missing molecular mechanism in the drugging process. The second system we apply EPR to is the transcription factor Nrf2, with the aim of characterizing the working mechanism of a key cellular self-defensive pathway centered on this transcription factor. Nrf2 has received increasing attention recently because, together with its binding partner Kelch-like ECH associated protein 1 (Keap1), it is found to be the key regulator in an antioxidant pathway against permanent neurological damage and multiple sclerosis. Of particular interest are changes in the structure and dynamics of the Nrf2-Keap1 complex upon interaction with various ligands, toxic or oxidant stresses, and clinical or potential drugs.

3. Understanding the structural basis of essential elastomeric biomaterials.

Elastomeric proteins play diverse andcrucial roles as rubber-like biomaterials in a variety of biological tissues. The mechanical properties of these biomaterials are often more desirable than analogous synthetic materials. The most intriguing properties of the elastomeric proteins are their ability to store and release energy upon deformation caused by the changing of external conditions, such as force, temperature, or water content. Intermolecular interaction/crosslinking among elastomeric proteins plays a key role in maintaining the unique macromolecular properties of these materials. At a molecular level, the driving force of such elasticity is found to be an entropy increase in the “relaxed” state compared to the “stressed” or the “stretched” state (Figs. 2A). We will use EPR in combination with a force device (Fig. 2B) to understand the structural basis of the molecular elasticity and to provide the structural basis of rational design of new biomaterials.

Figure 2

Figure 2. (A) Schematic description of the properties of biomaterials. The structural differences between the relaxed and the stretched states can be monitored by interspin distance measurement. (B) A combination of EPR and a force device to determine the structure and dynamics of biomaterials.

Open Positions

- Graduate Students and Undergraduate Students - Please contact me at if you are interested in our group. 
- Postdoctoral researchers - Please send me your CV and the names and contact information of three professional references at


Selected Publications

Corresponding author (as indicated by *).

  1. Y. Pan, S. Neupane, J. Farmakes, M. Bridges, K. Bentz, J. Rao, S.Y. Qian, G. Liu, Z. Yang,* “Probing the Structural Basis and Adsorption Mechanism of an Enzyme on Nano-sized Protein Carriers”, Submitted to Nanoscale, (2017), In press.
  2. S. Neupane, Y. Pan, S. Takalkar, K. Bentz, J. Farmakes, Y. Xu, B. Chen, G. Liu, S.Y. Qian, Z. Yang,* “Probing the aggregation mechanicsm of gold nanoparticles triggered by a globular protein”, The Journal of Physical Chemistry C, (2017), 121, 1377-1386.
  3. Y. Xu, X. Yang, P. Zhao, Z. Yang, C. Yan, B. Guo, and S. Y. Qian, “Knockdown of delta-5-desaturase promotes the anti-cancer activity of dihomo-γ-linolenic acid and enhances the efficacy of chemotherapy in colon cancer cells expressing COX-2”, Molecular Cancer Therapeutics, (2016), 96, 67-77.
  4. S. Sinha, Y. Mei, A. Ramanathan, K. Glover, Z. Yang, C. L Colbert, “Conformational Flexibility Enables the Function of a BECN1 Region Essential for Starvation-Mediated Autophagy”, The FASEB Journal, (2016), 1062.6-1062.6.
  5. Y. Mei, A. Ramanathan, K. Glover, C. Stanley, R. Sanishvili, S. Chakravarthy, Z. Yang, C. L Colbert, S. C Sinha “Conformational Flexibility Enables the Function of a BECN1 Region Essential for Starvation-Mediated Autophagy”, Biochemistry, (2016), 55, 1945-1958.

Publications based on work prior to NDSU.

  1. B. M. Stadtmueller, Z. Yang, K. E. Huey-Tubman, H. Roberts-Mataric, W. L. Hubbell, and P. J. Bjorkman, “Biophysical and biochemical characterization of avian secretory component provides structural insights into the evolution of the polymeric Ig receptor”, Journal of Immunology, (2016), 197, 1408-1414.
  2. Z. Yang, M. D. Bridges, C. J. López, O. Yu. Rogozhnikova, D. V. Trukhin, E. K. Brooks, V. Tormyshev, H. J. Halpern, W. L. Hubbell, “A Triarylmethyl Spin Label for Long-Range Distance Measurement at Physiological Temperatures Using T1 Relaxation Enhancement”, Journal of Magnetic Resonance, (2016), 269, 50-54.
  3. R. Guo, K. Gaffney, Z. Yang, M. Kim, S. Sungsuwan, X. Huang, W. L. Hubbell and H. Hong, “General steric trapping strategy reveals an intricate cooperativity network in the intramembrane protease GlpG under native condition”, Nature Chemical Biology. (2016), 12, 353-360.
  4. D. Davydov, Z. Yang, N. Davydova, J. Halpert, and W. L. Hubbell, “Cytochrome P450 3A4 transitions revealed in a pressure perturbation study by LRET and EPR spectroscopy”, Biophysical Journal. (2016), 110, 1485-1498.
  5. B. M. Stadtmueller, K. Huey-Tubman1, C. Lopez, Z. Yang, W. L. Hubbell, and P. J. Bjorkman, “The structure and dynamics of secretory component and its interactions with polymeric immunoglobulins”, elife. (2016), 5, e10640.
  6. R. O. Dror, T. J. Mildorf, D. Hilger, A. Manglik, D. W. Borhani, D. H. Arlow, A. Philippsen, Z. Yang, M. T. Lerch, W. L. Hubbell, B. K. Kobilka, R. K. Sunahara, and D. E. Shaw, “Structural basis for nucleotide exchange in heterotrimeric G proteins”, Science. (2015), 348, 1361-1365. (highlighted on 22 June, 2015, print issue of Chemical & Eng. News)
  7. M. Lerch, Z. Yang, C. Altenbach and W.L. Hubbell, “Measuring structure and dynamics of proteins using high pressure EPR spectroscopy”, Methods in Enzymology. (2015), 564, 29-57.
  8. Z. Yang, M. Bridges, M. Lerch, C. Altenbach and W.L. Hubbell, “Saturation recovery EPR spectroscopy in protein structure and dynamics determination”, Methods in Enzymology. (2015), 564, 3-27.
  9. Z. Yang, M. Ji, T. Cunningham and S. Saxena, “Cu2+ as an ESR probe of protein structure and function”, Methods in Enzymology. (2015), 563, 459-481.
  10. C. J. Lopez, M. Lerch, Z. Yang, J. Horwitz, M. Kreitman and W. L. Hubbell, “A structure-relaxation mechanism for the response of proteins to hydrostatic pressure”, Proc. Natl. Acad. Sci. USA. (2015), 112, E2437-E2446.
  11. A. Manglik, T. H. Kim, M. Masureel, C. Altenbach, Z. Yang, D. Hilger, T. S. Kobilka, F. S. Thian, W. L. Hubbell, R. S. Prosser, and B. K. Kobilka, “Structural insights into the dynamic process of β2-adrenergic receptor signaling”, Cell, (2015), 161, 1101-1110.
  12.  M. Bridges, Z. Yang, and Wayne Hubbell, “Analysis of saturation recovery amplitudes to identify conformational exchange in spin labeled proteins”, J. Magn. Reson. (2015), submitted.
  13. Z. Yang, G. Jimenez, C. Lopez, M. bridges, K. Houk, and W.L. Hubbell, “Long range distance measurement in proteins at physiological temperatures using Saturation-Recovery EPR”, J. Am. Chem. Soc.(2014), 136, 15356−15365 (JACS spotlights).
  14. M. C. Thompson, N. M. Wheatley, J. Jorda, M. R. Sawaya, S. D. Gidaniyan, H. Ahmed, Z. Yang, K. N. McCarty, J. P. Whitelegge, and T. O. Yeates, “Identification of a Unique Fe-S Cluster Binding Site in a Glycyl-Radical Type Microcompartment Shell Protein”, J. Mol. Biol. (2014), 426, 3287-3304.
  15.  J. Vendome, K. Felsovalyi, H. Song, Z. Yang, X. Jin, J. Brasch, O. Harrison, G. Ahlsen, F. Bahna, A Kaczynska, P. Katsamba, D. Edmond, W. L. Hubbell, L. Shapiro, and B. Honig, “Structural and energetic determinants of adhesive binding specificity in type I cadherins”, Proc. Natl. Acad. Sci. USA., (2014), 111, E4175-E4184.
  16. D. Davydov, Z. Yang, J. Halpert, and W. L. Hubbell, “Exploring enzyme conformational landscape with pressure-perturbation: allosteric rearrangements in P450 3A4 revealed with FRET and SDSL-EPR", The FASEB journal, (2014), Vol 28, n.1, Supplement, 796.16
  17. M. Lerch, Z. Yang, C. J. Lopez, C. Altenbach, and W. L. Hubbell, “Determination of the conformational states of myoglobin trapped at high pressure using double electron-electron resonance spectroscopy”, Proc. Natl. Acad. Sci. USA, (2014), 111, E1201–E1210.
  18. C. J. Lopez, Z. Yang, C. Altenbach and W. L. Hubbell, “Conformational selection and adaption in ligand binding to T4 lysozyme cavity mutants”, Proc. Natl. Acad. Sci. USA., (2013), 110, E4306–E4315.
  19. W. L. Hubbell, C. J. Lopez, C. Altenbach, and Z. Yang, “New frontiers in site directed spin labeling of proteins”, Curr. Opin. Struct. Biol. (2013),23, 725-733.
  20. Z. Yang, Y. Liu, P. Borbat, J. Zweier, J. Freed and W. L. Hubbell, “Pulsed dipolar spectroscopy for distance measurements in spin labeled proteins near physiological temperature”, J. Am. Chem. Soc. (2012), 134, 9950-9952.
  21. Z. Yang, M.R. Kurpiewski, M. Ji, J.E. Townsend, P. Mehta, L. Jen-Jacobson and S. Saxena, “ESR spectroscopy reveals a novel allosteric mechanism of Cu2+ inhibition of magnesium-dependent nuclease catalysis”, Proc. Natl. Acad. Sci. USA., (2012), 109, E993-E1000.
  22. Z. Yang, M. Ji and S. Saxena, “Practical aspects of copper ion-based double electron electron resonance distance measurements”, Appl. Magn. Reson., (2011), 39, 487-500.
  23. Z. Yang, D. Kise and S. Saxena, “An approach towards the measurement of nanometer range distances based on Cu(II) ions and ESR”, J. Phys. Chem. B. (2010), 114, 6165–6174.
  24. Z. Yang, J. S. Becker and S. Saxena, “On Cu(II)-Cu(II) distance measurements using pulsed electron electron double resonance", J. Magn. Reson.(2007), 188, 337-343.


Zhongyu Yang

Assistant Professor

BS, University of Science and Technology of China 2004
PhD, University of Pittsburgh 2010
Post-doctoral Fellow, University of California, Los Angeles 2010-2015

Office: Dunbar 61
tel: 701-231-8639
fax: 701-231-8831