Nikolay Dokholyan, PhD

RESEARCH INTERESTS:

Computational Structural Biology and Biophysics

Our group focuses primarily on understanding the structure and dynamics of biological molecules and their complexes and on how induced changes in structure and dynamics lead to disease. One prominent example of this is the hypothesized misfolding of superoxide dismutase associated with the neurodegenerative disease Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease. The lab is currently pursuing the specific directions among others (see details at http://dokhlab.unc.edu/):

I. Molecular Etiology of ALS
Mutations in the dimeric enzyme superoxide dismutase (SOD1) have been linked to familial (hereditary) cases of ALS. Formation of toxic SOD1 aggregates is associated with both sporadic and familial ALS. Our group aims to uncover the origin of mutant SOD1 toxicity at the molecular level by using a combination of computational and experimental approaches. Approximately 10% of ALS patients suffer from a familial form of ALS. Because the SOD1 mutations in these patients are thought to cause SOD1 aggregation, we plan to (i) determine whether these mutations facilitate aggregation by altering the balance between native and misfolded states (ii) determine the effect of refolding factors (chaperones) on mutant SOD1 folding, and (iii) reconstruct the SOD1 aggregates computationally. We plan to identify the structure of SOD1 aggregates using Discrete Molecular Dynamics (DMD), a tool for rapid simulations of simplified protein models. Determining the structure of SOD1 aggregates is critical for designing small molecules that can prevent or reverse the formation of these toxic aggregates.
 

II. The Protein Folding Problem

A fundamental goal of molecular biophysics is to understand the relationship between protein sequence and structure, also known as the protein folding problem. Solving this problem is critical for making accurate protein structure/function predictions. In order to address this problem computationally, it is necessary to develop an inter-atomic interaction potential. We are developing a hierarchy of interaction models, from simplified coarse-grained models to more detailed ones, and determining their interaction parameters. These interaction models are then used to perform simulations of protein models using a range of molecular dynamics simulations methodologies designed to accommodate the interaction models. The advantage of this approach is its modularity; instead of solving the much more difficult problem of finding a native state by spanning the whole protein folding time scale, one can separate the time scale out into slow and fast events in protein folding and treat them with different methodologies.

III. Chromatin Structure and Dynamics

In eukaryotic cells, gene expression in addition to other DNA-templated processes such as recombination, repair, and chromosome segregation are controlled in large part through the regulation of chromatin structure and DNA accessibility. At the heart of chromatin structure is the nucleosome core particle, which is comprised of DNA and histone proteins. Chromatin structure and dynamics are fundamentally dictated by the function of individual nucleosomes, which can be modified by incorporation of histone variants and post-translational modifications. Yet how variant histones and other chromatin modifications affect chromatin organization to regulate DNA function is poorly understood, due in part to the lack of tools to study chromatin at an intermediate scale. To address this problem, we have developed a novel interdisciplinary approach for multiscale computational modeling of nucleosomal chromatin. We work in an interdisciplinary team that that combines genetic, biochemical, cytological, and biophysical experiments with our computational approaches. Throughout our studies, the experimental information is used to refine and further develop high-resolution computational models of chromatin. Understanding how chromatin structure influences transcription and chromosome behavior will elucidate fundamental processes that are associated with many human cancers, aging, and developmental defects.

RECENT PUBLICATIONS:

L. He, A. W. R. Serohijos, T. Hegedus, L. A. Aleksandrov, L. Cui, A. A. Aleksandrov, N. V. Dokholyan, and J. R. Riordan, "Multiple membrane-cytoplasmic domain contacts in CFTR" Journal of Biological Chemistry, in press (2008)

C. Ozvegy-Laczka, R. Laczko, C. Hegedus, T. Litman, G. Varady, K. Goda, T. Hegedus, N. V. Dokholyan, B. P. Sorrentino, A. Varadi, and B. Sarkadi, "Interaction with the 5D3 monoclonal antibody is regulated by intramolecular rearrangements but not by covalent dimer formation of the human ABCG2 multidrug transporter" Journal of Biological Chemistry, in press (2008)

S. Yin, L. Biedermannova, J. Vondrasek, and N. V. Dokholyan, "MedusaScore: An accurate force-field based scoring function for virtual drug screening" Journal of Chemical Information and Modeling, in press (2008)

S. Sharma, F. Ding, and N. V. Dokholyan, "iFoldRNA: Three-dimensional RNA structure prediction and folding" Bioinformatics, in press (2008)

J. Hao, A. W. R. Serohijos, G. Newton, G. Tassone, Z. Wang, D. C. Sgroi, N. V. Dokholyan, and J. P. Basilion, "Identification and rational redesign of peptide ligands to CRIP1, a novel biomarker for cancers" Public Library of Science Computational Biology, in press (2008)

G. Meissner, D. A. Pasek, N. Yamaguchi, S. Ramachandran, N. V. Dokholyan, and A. Tripathy, "Thermodynamics of calmodulin binding to cardiac and skeletal muscle ryanodine receptor ion channels" Proteins: Structure, Function, and Bioinformatics, in press (2008)

Y. Chen and N. V. Dokholyan, "Natural selection against protein aggregation on self-interacting and essential proteins in yeast, fly and worm" Molecular Biology and Evolution, 25: 1530-1533 (2008)

D. G. Teotico, M. Frazier, F. Ding, N. V. Dokholyan, B. Temple, and M. R. Redinbo, "Active nuclear receptors exhibit highly correlated AF-2 domain motions" Public Library of Science Computational Biology, 4: e1000111 (2008)

F. Ding, D. Tsao, H. Nie, and N. V. Dokholyan, "Ab initio folding of proteins with all-atom discrete molecular dynamics" Structure, 16: 1010-1018 (2008)

T. Hegedus, A. W. R. Serohijos, N. V. Dokholyan, L. He, and J. R. Riordan, "Computational studies reveal phosphorylation dependent changes in the unstructured R domain of CFTR" Journal of Molecular Biology, 378: 1052-1063 (2008)

F. Ding, S. Sharma, P. Chalasani, V. V. Demidov, N. E. Broude, and N. V. Dokholyan, "Large scale simulations of 3D RNA folding by discrete molecular dynamics: From structure prediction to folding mechanisms" RNA, 14: 1164-1173 (2008)

A. W. R. Serohijos, T. Hegedus, A. A. Aleksandrov, L. He, L. Cui, N. V. Dokholyan, and J. R. Riordan, "Phenylalanine 508 forms an interdomain contact in the CFTR structure crucial to folding and function" Proceedings of the National Academy of Sciences USA, 105: 3256-3261 (2008)

A. W. R. Serohijos, T. Hegedus, J. R. Riordan, and N. V. Dokholyan, "Diminished self-chaperoning activity of the ΔF508 mutant CFTR results in protein misfolding" Public Library of Science Computational Biology, 4: e1000008 (2008)

S. Sharma, F. Ding, and N. V. Dokholyan, "Probing protein aggregation using simplified models and discrete molecular dynamics" Frontiers in Bioscience, 13: 4795-4808 (2008)

S. Sharma and N. V. Dokholyan, "DNA sequence mediates nucleosome structure and stability" Biophysical Journal, 94: 1-3 (2008)

Y. Chen, F. Ding, H. Nie, A. W. Serohijos, S. Sharma, K. C. Wilcox, S. Yin, and N. V. Dokholyan, "Protein folding: then and now" Archives of Biochemistry and Biophysics, 469: 4-19 (2008)

S. Yin, F. Ding, and N. V. Dokholyan, "Modeling backbone flexibility improves protein stability estimation" Structure, 15: 1567-1576 (2007)

A. R. Lam, J. M. Borreguero, F. Ding, N. V. Dokholyan, S. V. Buldyrev, E. I. Shakhnovich, H. E. Stanley, "Parallel folding pathways in the Src SH3 domain" Journal of Molecular Biology, 373: 1348-1360 (2007)

S. Sharma, P. Gong, B. Temple, D. Bhattacharyya, N. V. Dokholyan, and S. G. Chaney, "Molecular dynamic simulations of cisplatin- and oxaliplatin-d(GG) intrastand cross-links reveal differences in their conformational dynamics" Journal of Molecular Biology, 373: 1123-1140 (2007)

S. D. Khare and N. V. Dokholyan, "Molecular mechanisms of polypeptide aggregation in human diseases" Current Protein & Peptide Science, 8: 573-579 (2007)

S. Barton, R. Jacak, S. D. Khare, F. Ding, and N. V. Dokholyan, "The length dependence of the polyQ-mediated protein aggregation" Journal of Biological Chemistry, 282: 25487-25492 (2007)

Y. Chen, S. L. Campbell, and N. V. Dokholyan, "A constraint-free method for selecting protein conformations consistent with NMR dynamics data" Biophysical Journal, 93: 2300-2306 (2007)

S. Yin, F. Ding, and N. V. Dokholyan, "Eris: An automated estimator of protein stability" Nature Methods, 4: 466-467 (2007)

Y. Chen, F. Ding, and N. V. Dokholyan, "Fidelity of protein structure reconstruction from inter-residue proximity constraints" Journal of Physical Chemistry B, 111: 7432-7438 (2007)

C. Davis, H. Nie, and N. V. Dokholyan, "Insights into thermophilic archaebacterial membrane stability from simplified models of lipid membranes" Physical Review E, 75: 051921 (2007)

S. Sharma, F. Ding, and N. V. Dokholyan, "Multi-scale modeling of nucleosome dynamics" Biophysical Journal, 92 1457-1470 (2007)

B. Podobnik, J. Shao, N. V. Dokholyan, V. Zlatic, H. E. Stanley, I. Grosse, "Similarity and dissimilarity in correlations of genomic DNA" Physica A, 373: 497-502 (2007)

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, 103: 18540-18545 (2006)

E. V. Petrotchenko, D. Pasek, P. Elms, N. V. Dokholyan, G. Meissner, and C. H. Borchers, “Combining fluorescence detection and mass spectrometric analysis for comprehensive and quantitative analysis of redox-sensitive cysteines in native membrane proteins” Analytical Chemistry, 78: 7959-7966 (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, 22: 2693-2694 (2006)

Y. Chen and N. V. Dokholyan, "Insights into allosteric control of vinculin function from its large-scale conformational dynamics" Journal of Biological Chemistry, 281: 29148-29154 (2006)

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, 13: 226 - 235 (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]

Y. Chen and N. V. Dokholyan, "The coordinated evolution of yeast proteins constrained by functional modularity" Trends in Genetics, 22: 416-419 (2006)

K. Bloom, S. Sharma, and N. V. Dokholyan, "The path of DNA in the kinetochore" Current Biology, 16: R276-R278 (2006)

S. D. Khare and N. V. Dokholyan, "Common dynamical signatures of FALS-associated structurally-diverse Cu, Zn superoxide dismutase mutants" Proceedings of the National Academy of Sciences USA, 103: 3147-3152 (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" Proceedings of the National Academy of Sciences USA, 103: 2052-2056 (2006).

N. V. Dokholyan, "Studies of folding and misfolding using simplified models", Current Opinion in Structural Biology, 16: 79-85 (2006).

F. Ding, K. C. Prutzman, S. L. Campbell, and N. V. Dokholyan, "Topological determinants of protein domain swapping", Structure, 14: 5-14 (2006).
[Adobe PDF][Portal: H-predictor]

F. Ding, S. 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).

N. V. Dokholyan, "The architecture of the protein domain universe" Gene, 347: 199-205 (2005); q-bio.MN/0408006.

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 Biotechnology, 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: Structure, Function, and Bioinformatics, 61: 617-632 (2005).
[Adobe PDF]

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", Public Library of Science Computational Biology, 1: e30 (2005) [Cover article].

Y. Chen and N. V. Dokholyan, "A single disulfide bond differentiates aggregation pathways of ß2-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).