Nikolay Dokholyan

Research: Computation/Experimental biophysics and structural biology

Nikolay Dokholyan

Michael Hooker Distinguished Professor of Biochemistry and Biophysics
(PhD - Boston University)

120 Mason Farm Road, CB# 7260
3097 Genetic Medicine Building
Chapel Hill, NC 27599-7260

Dokholyan Lab Website


  • Michael Hooker Distinguished Professorship, 2014
  • American Physical Society Fellow, 2013
  • March of Dimes Basil O'Connor Starter Scholar Research Award, 2004-2006
  • The University of North Carolina at Chapel Hill IBM Junior Faculty Development Award, 2004
  • UNC Research Council Award, 2003
  • NIH postdoctoral fellowship, 1999-2002


Molecular etiologies of human diseases

My laboratory focuses on understanding etiologies of human diseases, such as cystic fibrosis (CF), amyotrophic lateral sclerosis (ALS), and conditions, such as hyperalgesia. My lab has utilized several integrated computational and experimental strategies to understand, sense (recognize and report), and control aberrant biological molecules, and uncover etiologies of human diseases. We have developed approaches to molecular structural modeling and dynamic simulations, allowing study of structure and dynamics of biological molecules at time scales relevant to biological systems. These approaches uniquely distinguish my laboratory from others because they integrate rapid physical dynamics simulations, experiments, and molecular modeling and design, allowing us to make significant breakthroughs in understanding etiologies of CF and ALS. The translational research in my laboratory is based on our developed methodologies described below.

Methodologies. Molecular structure and dynamics underlies all biological processes. Most research in biomedical fields is directly or indirectly associated with molecular behavior. In the field of biochemistry, experimental approaches have been directly targeting these molecular properties, albeit within a specific “window” of observable length and time scales. Computational approaches can offer much wider windows, but present only hypotheses about the system rather than “real” observables. Integrated computational and experimental approaches, therefore, present unparalleled strategies for exploring biological systems, a philosophy that has guided us in my laboratory.

Perhaps the most outstanding challenge in computational biology is sampling of molecular conformational states. Most research in my laboratory has been dedicated to solving this critical problem. We achieved this goal by developing rapid discrete molecular dynamics simulations, novel and unique in the level of accuracy molecular docking algorithm that we have already used to find novel lead compounds to treat CF and reduce chronic and acute pain (in both cases these compounds are been pursued by biotech companies).  We are currently pursuing understanding of other human diseases and developing novel pharmaceutical strategies to combat them, and actually searching for compounds using a combination of virtual drug screening and experiment. Application of these tools also allows rational design of proteins that can control other proteins in living cells and organisms. These tools are becoming invaluable resources that enables decoupling cellular networks, as well understanding the impact of a specific protein on the phenotype of an organism.

RECENT PUBLICATIONS  pubmed.png (click for Full Publication List)

  • Proctor, E. A., Kota, P., Aleksandrov, A. A., He, L., Riordan, J. R., Dokholyan, N. V. "Rational coupled dynamics network manipulation rescues disease-relevant mutant cystic fibrosis transmembrane regulator", Chemical Science, 6:1237-1246 (2015)
  • Brown, K. A., Zou, D., Shirvanyants, D., Zhang, J., Samanta, P. K., Dokholyan, N. V., and Deiters, A. "Light-cleavable rapamycin dimer as an optical trigger for protein dimerization", Chemical Communications, 51:5702-5705 (2015)
  • Kota, P., Buchner, G., Chakrabarty, H., Dang, Y. L., Hong, H., Garcia, G. J. M., Kubelka, J., Gentzsch, M., Stutts, M. J., and Dokholyan, N. V. "The N-terminal domain allosterically regulates cleavage and activation of the epithelial sodium channel", Journal of Biological Chemistry, 289:23029-23042 (2014)
  • Cholon, D. M., Quinney, N. L., Fulcher, M. L., Esther, C. R., Das, J., Randell, S. H., Dokholyan, N. V., Boucher, R. C., and Gentzsch M. "Potentiator ivacaftor abrogates pharmacological correction of ΔF508 CFTR in cystic fibrosis", Science Translational Medicine, 6:246ra96 (2014)
  • Shirvanyants, D., Ramachandran, S., Mei, Y., Xu, L., Meissner, G., Dokholyan, N. V. "Pore dynamics and conductance of RyR1 transmembrane domain", Biophysical Journal, 106:2375-2384 (2014)
  • Redler, R. L., T. Fee, l., Fay, J., Caplow, M., Dokholyan, N. V. "Non-native soluble oligomers of Cu/Zn superoxide dismutase (SOD1) contain a conformational epitope linked to cytotoxicity in amyotrophic lateral sclerosis (ALS)", Biochemistry, 53:2423-2432 (2014)
  • Dagliyan, O., Shirvanyants, D., Karginov, A., Ding, F., Fee, L., Chandrasekaran, S. N., Freisinger, C. M., Smolen, G. A., Huttenlocher, A., Hahn, K. M., and Dokholyan, N. V. "Rational design of a ligand-controlled protein conformational switch", Proceedings of the National Academy of Sciences USA, 110:6800-6804 (2013)
  • Kota, P., Garcia-Caballero, A., Dang, H., Gentzsch, M., Stutts, M. J. and Dokholyan, N. V. "Energetic and structural basis for activation of the epithelial sodium channel by matriptase", Biochemistry, 51:3460-3469 (2012)
  • Ding, F., Lavender, C. A., Weeks, K. M. and Dokholyan, N. V. "Three-dimensional RNA structure refinement by hydroxyl radical probing", Nature Methods, 9:603-608 (2012)
  • Shirvanyants, D., Ding, F., Tsao, D., Ramachandran, S. and Dokholyan, N. V. "DMD: an efficient and versatile simulation method for fine protein characterization", Journal of Physical Chemistry B, 116:8375-8382 (2012)
  • Ding, F., Furukawa, Y., Nukina, N., and Dokholyan, N. V. "Local unfolding of Cu, Zn Superoxide Dismutase monomer determines the morphology of fibrillar aggregates", Journal of Molecular Biology, 421:548-560 (2012)
  • Proctor, E. A., Yin, S., Tropsha, A., and Dokholyan, N. V. "Discrete molecular dynamics distinguishes native-like binding poses from decoys in difficult targets", Biophysical Journal, 102:144-151 (2012)

Lab Contact:

Lab Rooms: 3100 C-D Genetic Medicine
Lab Phone: 919-966-6781
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