Last Updated: 12/18/2008

Research Interests
I. Overview of professional objectives

Approaches to medicine are rapidly changing as we begin to comprehend human disease at the most fundamental molecular level. Much of this change is heralded by a more quantitative and mechanistic understanding of the alterations of molecular structure and dynamics that produce disease. Because of this transition towards a more quantitative view, a large breadth of approaches developed for other fields can now be applied to fighting disease. As a trained physicist with a background in studies of complex systems, I feel that physics the natural science of matter and interactions offers a wide range of methodologies designed to understand complex systems at the atomic and molecular levels. My career goal is to use my quantitative and computational skills to study complex, medically-relevant biological systems, understand the molecular origins of human diseases, and ultimately contribute to the development of new therapeutic strategies to rationally abate disease. I aim to uncover the roles of molecular structure and dynamics in certain cellular processes leading to human diseases.

Recent years have brought a dramatic increase in the number of known associations between human disease and abnormalities in protein dynamics and structure. In particular, the number of diseases known to be associated with protein misfolding has increased several-fold. Since protein structure and dynamics are intimately related to protein cellular function, abnormalities in protein folding dynamics and structural stability often adversely affect cell life. I believe that understanding protein folding and misfolding will be vital to understanding human diseases, ranging from various forms of cancer to neurodegenerative diseases, and will facilitate the development of therapeutic strategies to combat these diseases.

I plan to dedicate my efforts to pioneering multidisciplinary methods for determining dynamic molecular structure ensembles and molecular complexes, particularly those not amenable to direct experimental approaches. My laboratory consists of student and postdoctoral members of the Physics, Biochemistry & Biophysics, Computer Science, Medicinal Chemistry, and Biomedical Engineering Departments. In addition to the multidisciplinary nature of my laboratory, I have forged broad collaborations spanning multiple disciplines across the University of North Carolina at Chapel Hill campus and at other academic institutions.


II. An emerging view of protein structure the need for new tools

Since the first structure determination of myoglobin in 1959 by Kendrew, our thinking of protein structure has changed. An emerging view of protein structure is actually that of an ensemble of protein conformations, some of which determine specific protein functions. Protein dynamics determines how often these functionally important protein conformations appear in the course of protein life, and, therefore, modulates its functional activity. Despite recent revolutionary advances in experimental methodologies, we are still limited in our ability to sample and decipher the structural and dynamic aspects of single molecules that are critical for their biological function. Thus, there is a crucial need for new and unorthodox techniques to uncover the fundamentals of molecular structure and interactions.

Cellular life is organized hierarchically: while proteins have specific functions (e.g. specific enzymatic reactions), protein complexes represent higher-level functional modules responsible for large-scale events in cellular life (e.g. DNA transcription). Molecular complexes are often dynamic they appear in various forms at various stages of their functional life. Understanding the detailed structures of these large molecular assemblies and their dynamics is necessary to developing a higher-level understanding of cellular biology. However, atomic-level determination of these assemblies has been out of reach to experiments and computation, and will remain a main challenge for years to come. Thus, a revolution in uncovering the structure and dynamics of these complexes will require a deep theoretical understanding of atomic interactions. Since atomic interactions are a focus of the field of physics, my area of specialty, I believe I have the appropriate set of skills to study the structure and dynamics of molecules and molecular complexes.

Dynamic features of molecular complexes, particularly large complexes, are often inaccessible to current experimental techniques due to their inherent resolution limitations in length and time scales. Computational approaches offer a unique opportunity to bridge the size and timescale gaps and uncover the atomic structure and biological properties of these experimentally invisible molecules and molecular complexes. I believe that a symbiosis of experimental and computational approaches is ideal for refining our insights into the structure and conformational dynamics of molecules and molecular complexes. A powerful iterative process could combine development of new computational tools with experimental verification of these tools. I plan to design a hierarchy of computational models, of increasing complexity, that will capture and capitalize on the fundamental principles governing molecular interactions. These models, that will span the hierarchy of molecular structure, will offer hypotheses that will then be experimentally tested. Feedback from the experiments will permit further development of higher-complexity models. Any common thread we find throughout the hierarchy of models will offer theoretical insights into molecular organization. Based on the developed knowledge of molecular structure, we will then search for novel pharmaceutical treatment strategies.


III. Relevance to cancer research

Currently there are several projects in my laboratory are directly related to cancer research. We study the dynamics of cancer-related cell signaling proteins (in collaboration with Prof. Sharon Campbell (UNC-CH, Biochemistry & Biophysics) and Prof. Klaus Hahn (UNC-CH, Pharmacology)), such as focal adhesion kinase (Dixon et al, Structure 2004, Ding et al, Structure 2006), vinculin (Chen & Dokholyan, Journal of Biological Chemistry 2006) , and Ras (Wu et al, in preparation 2006), in attempt to understand their function and mechanisms of their activation. In collaboration with Prof. Christoph Borchers (UNC-CH, Biochemistry & Biophysics) we study structural organization of the anaphase promoting complex. In collaboration with Prof. Stephen Chaney (UNC-CH, Biochemistry & Biophysics) we investigate the effect of the FDA approved platinum drugs oxaliplatin and cisplatin on metastatic colon cancer (research is funded by the NIH).

In collaboration with Prof. Brian Kuhlman (UNC-CH, Biochemistry & Biophysics) we are developing, a method for rationally designing and synthetically producing antibodies (research is funded by the DARPA). In collaboration with Prof. Alex Tropsha (UNC-CH, Medicinal Chemistry) we developed a screening algorithm that utilizes recent advances in computational physics and chemistry to rank a large library of chemically-active compounds against their abilities to inhibit protein dissociation. In collaboration with Prof. Natalia Broude (Boston University) we are developing GFP-based biological sensors. We have also assembled a team on UNC-CH campus to study chromatin structural organization and factors that regulate gene transcription (with Profs. Brian Strahl (Biochemistry & Biophysics), Jason Lieb (Biology), Kerry Bloom (Biology), Garegin Papoian (Chemistry), and Mayetri Gupta (Biostatistics)) (research is currently funded by NCBC).

Recent Accomplishments and Honors
1990-1994 Recipient of Honorary Stipend, Moscow Institute of Physics and Technology
1994 "Red Diploma" 1994 (in Former USSR "Red Diploma" is awarded for outstanding achievements)
1995, 1998, 2001, 2006 NSF Young Scientist Travel Award
1998-1999 NIH Molecular Biophysics Predoctoral Traineeship
1999-2002 NIH postdoctoral fellowship
2004 The University of North Carolina at Chapel Hill IBM Junior Faculty Development Award
2004-2006 Basil OConnor Starter Scholar Research Award

Training
Moscow Institute of Physics and Technology B.S. 1992 Physics
Moscow Institute of Physics and Technology M.S. 1994 Physics
Boston University Ph.D. 1999 Physics
Harvard University NIH Postdoc 1999-2002 Biophysics

Publications
N. V. Dokholyan, Lewyn Li, Feng Ding, and E. I. Shakhnovich, "Topological determinants of protein folding." PNAS 99 8637-8641 (2002)
N. V. Dokholyan, B. Shakhnovich, and E. I. Shakhnovich, "Expanding protein universe and its origin from biological Big Bang." PNAS 99: 14132-14136 (2002)
N. V. Dokholyan, "What is the protein design alphabet?" Proteins, 54: 622-628 (2003)
S. Khare, F. Ding, and N. V. Dokholyan, "Folding of Cu, Zn superoxide dismutase and Familial Amyotrophic Lateral Sclerosis." Journal of Molecular Biology 334: 515-525 (2003)
J. Khatun, S. D. Khare, and N. V. Dokholyan, "Can contact potentials reliably predict stability of proteins?" Journal of Molecular Biology, 336: 1223-1238 (2004)
B. Urbanc, L. Cruz, F. Ding, D. Sammond, S. Khare, S. V. Buldyrev, H. E. Stanley, and N. V. Dokholyan, "Molecular dynamics simulation of Amyloid β dimer formation." Biophysical Journal, 87: 2310-2321 (2004)
S. D. Khare, M. Caplow, and N. V. Dokholyan, "The rate and equilibrium constants for a multi-step reaction sequence for the aggregation of superoxide dismutase in ALS." PNAS 101: 15094-15099 (2004)
R. D. S. Dixon, Y. Chen, F. Ding, S. D. Khare, K. C. Prutzman, M. D. Schaller, S. L. Campbell, and N. V. Dokholyan, "Reconstructing folding intermediates of the focal adhesion targeting domain of Focal Adhesion Kinase." Structure, 12: 2161-2171 (2004)
F. Ding, Sergey V. Buldyrev, and N. V. Dokholyan, "Folding Trp-cage to NMR resolution native structure using a coarse-grained protein model." Biophysical Journal, 88: 147-155 (2005)
F. Ding, R. K. Jha, and N. V. Dokholyan, "Scaling behavior and structure of denatured proteins." Structure, 13: 1047-1054 (2005) [Cover article]
F. Ding and N. V. Dokholyan, "Simple but predictive protein models." Trends in Biotech., 23: 450-455 (2005)
S. D. Khare, K. C. Wilcox, P. Gong, and N. V. Dokholyan, "Sequence and structural determinants of Cu, Zn superoxide dismutase aggregation." Proteins, 61: 617-632 (2005)
F. Ding, W. Guo, N. V. Dokholyan, E. I. Shakhnovich, and J.-E. Shea, "Reconstruction of the src-SH3 protein domain transition state ensemble using multiscale molecular dynamics simulations." Journal of Molecular Biology, 350: 1035-1050 (2005)
S. D. Khare, F. Ding, K. N. Gwanmesia, and N. V. Dokholyan, "Molecular origin of polyglutamine-mediated protein aggregation in neurodegenerative diseases" PLoS Computational Biology, 1: e30 (2005) [Cover article]
Y. Chen and N. V. Dokholyan, "A single disulfide bond differentiates aggregation pathways of 2-microglobulin", Journal of Molecular Biology, 354: 473-482 (2005)
F. Ding, J. J. Larocque, and N. V. Dokholyan, "Direct observation of protein folding, aggregation, and a prion-like conformational conversion" Journal of Biological Chemistry, 280: 40235-40240 (2005)
F. Ding, K. C. Prutzman, S. L. Campbell, and N. V. Dokholyan, "Topological determinants of protein domain swapping" Structure, 14: 5-14 (2006)
N. V. Dokholyan, "Studies of folding and misfolding using simplified models", Current Opinion in Structural Biology, 16: 79-85 (2006)
V. V. Demidov, N. V. Dokholyan, C. Witte-Hoffman, P. Chalasani, H.-W. Yiu, F. Ding, Y. Yu, C. R. Cantor, N. E. Broude, "Fast complementation of split fluorescent protein triggered by DNA hybridization" PNAS, 103: 2052-2056 (2006)
S. D. Khare and N. V. Dokholyan, "Common dynamical signatures of FALS-associated structurally-diverse Cu, Zn superoxide dismutase mutants" PNAS, 103: 3147-3152 (2006)
K. Bloom, S. Sharma, and N. V. Dokholyan, "The path of DNA in the kinetochore" Current Biology, 16: R276-R278 (2006)
Y. Chen and N. V. Dokholyan, "The coordinated evolution of yeast proteins constrained by functional modularity" Trends in Genetics, 22: 416-419 (2006)
F. Ding and N. V. Dokholyan, "Emergence of protein fold families through rational design" Public Library of Science Computational Biology, 2: e85 (2006) [Cover article]
S. D. Khare, M. Caplow, and N. V. Dokholyan, "FALS mutations in Cu, Zn superoxide dismutase destabilize the dimer and increase dimer dissociation propensity: a large-scale thermodynamic analysis." Amyloid: the Journal of Protein Folding Disorders, in press (2006)
Y. Chen and N. V. Dokholyan, "Insights into allosteric control of vinculin function from its large-scale conformational dynamics" Journal of Biological Chemistry in press (2006)
S. Sharma, F. Ding, H. Nie, D. Watson, A. Unnithan, J. Lopp, D. Pozefsky, and N. V. Dokholyan, "iFold: A platform for interactive folding simulations of proteins" Bioinformatics in press (2006)
A. W. Serohijos, Y. Chen, F. Ding, T. C. Elston, and N. V. Dokholyan, "A new structural model reveals energy transduction in dynein" Proceedings of the National Academy of Sciences USA in press (2006)

E-mail: dokh@med.unc.edu
Telephone: 843-2513
FAX: 966-2852
Address: 303 Mary Ellen Jones Bldg. Chapel Hill, NC 27599

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