Researcher Profile

Researcher Profile

Nikolay Dokholyan, PhD, MS

Nikolay Dokholyan, PhD, MS

G. Thomas Passananti Professor and Vice Chair for Research, Department of Pharmacology
Professor, Department of Biochemistry and Molecular Biology
Penn State Neuroscience Institute
Scientific Program:Next-Generation Therapies

Research Interests

The mission of Dr. Nikolay Dokholyan's laboratory is to develop and apply integrated computational and experimental strategies to understand, sense and control misfolded proteins in order to uncover the etiologies of human neurodegenerative diseases and develop therapeutics to fight them.

The lab aims to understand the molecular disease mechanisms of ALS: How does the misfolding of superoxide dismutase (SOD1) lead to the formation of toxic oligomeric intermediates? Using biochemical and biophysical approaches and innovative computation, the Dokholyan lab determined putative structures of SOD1 oligomers and is currently elucidating the downstream pathways that lead to motorneuron death. Structures of toxic oligomers provide targets for drug discovery, which the lab is pursuing.

Neurodegenerative diseases such as ALS, Alzheimer’s, Huntington’s, Parkinson’s and prion diseases share similar processes associated with protein misfolding and aggregation. These similarities suggest common pathways leading to neuron death that eventually result in a disease. The lab is working toward understanding the general principles of protein misfolding in neurodegenerative diseases through computational and experimental approaches.

To sense and control protein conformations, the lab is working toward development of genetically-encoded proteins that bind and report rare/intermediate conformations of target molecules or alter their state using drugs or light.

One of the critical components of the lab's integrative research is drug discovery, focusing on both biological therapeutics and small molecule screening. The lab developed a fully flexible docking algorithm, MedusaDock, that allows for virtual screening of compounds and is is an important asset for small molecule drug discovery efforts.

The lab has developed novel approaches to molecular dynamics simulations and modeling, allowing studies of biological molecules at time scales relevant to biological systems. These approaches synergistically integrate rapid dynamics simulations, molecular modeling and design, and biochemical and cellular biology experiments, allowing for significant strides in understanding the etiology of misfolding diseases.

  • Proteins
  • Molecular Dynamics Simulation
  • Mutation
  • RNA
  • Ligands
  • Superoxide Dismutase-1
  • Thermodynamics
  • Protein Folding
  • Amyotrophic Lateral Sclerosis
  • Peptides
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Ryanodine Receptor Calcium Release Channel

Recent Publications


Piltonen, M, Krokhotin, A, Parisien, M, Bérubé, P, Djambazian, H, Sladek, R, Dokholyan, NV, Shabalina, SA & Diatchenko, L 2020, 'Alternative Splicing of Opioid Receptor Genes Shows a Conserved Pattern for 6TM Receptor Variants', Cellular and Molecular Neurobiology.
Piltonen, M, Krokhotin, A, Parisien, M, Bérubé, P, Djambazian, H, Sladek, R, Dokholyan, NV, Shabalina, SA & Diatchenko, L 2020, 'Correction to: Alternative Splicing of Opioid Receptor Genes Shows a Conserved Pattern for 6TM Receptor Variants (Cellular and Molecular Neurobiology, (2020), 10.1007/s10571-020-00971-7)', Cellular and Molecular Neurobiology.
Dinavahi, SS, Gowda, R, Gowda, K, Bazewicz, CG, Chirasani, VR, Battu, MB, Berg, A, Dokholyan, NV, Amin, S & Robertson, GP 2020, 'Development of a Novel Multi-Isoform ALDH Inhibitor Effective as an Antimelanoma Agent', Molecular cancer therapeutics, vol. 19, no. 2, pp. 447-459.
Dokholyan, NV 2020, 'Experimentally-driven protein structure modeling', Journal of Proteomics, vol. 220, 103777.
Jiang, H, Fan, M, Wang, J, Sarma, A, Mohanty, S, Dokholyan, NV, Mahdavi, M & Kandemir, MT 2020, 'Guiding conventional protein-ligand docking software with convolutional neural networks', Journal of Chemical Information and Modeling, vol. 60, no. 10, pp. 4594-4602.
Makepeace, KAT, Brodie, NI, Popov, KI, Gudavicius, G, Nelson, CJ, Petrotchenko, EV, Dokholyan, NV & Borchers, CH 2020, 'Ligand-induced disorder-to-order transitions characterized by structural proteomics and molecular dynamics simulations', Journal of Proteomics, vol. 211, 103544.
Wang, J, Jain, A, McDonald, LR, Gambogi, C, Lee, AL & Dokholyan, NV 2020, 'Mapping allosteric communications within individual proteins', Nature communications, vol. 11, no. 1, 3862.
Zhang, DY, Wang, J & Dokholyan, NV 2020, 'Prefusion spike protein stabilization through computational mutagenesis', Proteins: Structure, Function and Bioinformatics.
Miao, Z, Adamiak, RW, Antczak, M, Boniecki, MJ, Bujnicki, J, Chen, SJ, Cheng, CY, Cheng, Y, Chou, FC, Das, R, Dokholyan, NV, Ding, F, Geniesse, C, Jiang, Y, Joshi, A, Krokhotin, A, Magnus, M, Mailhot, O, Major, F, Mann, TH, Piątkowski, P, Pluta, R, Popenda, M, Sarzynska, J, Sun, L, Szachniuk, M, Tian, S, Wang, J, Wang, J, Watkins, AM, Wiedemann, J, Xiao, Y, Xu, X, Yesselman, JD, Zhang, D, Zhang, Y, Zhang, Z, Zhao, C, Zhao, P, Zhou, Y, Zok, T, Żyła, A, Ren, A, Batey, RT, Golden, BL, Huang, L, Lilley, DM, Liu, Y, Patel, DJ & Westhof, E 2020, 'RNA-Puzzles round IV: 3D Structure predictions of four ribozymes and two aptamers', RNA, vol. 26, no. 8.
Wu, HD, Kikuchi, M, Dagliyan, O, Aragaki, AK, Nakamura, H, Dokholyan, NV, Umehara, T & Inoue, T 2020, 'Rational design and implementation of a chemically inducible heterotrimerization system', Nature methods, vol. 17, no. 9, pp. 928-936.
Xu, L, Harms, FL, Chirasani, VR, Pasek, DA, Kortüm, F, Meinecke, P, Dokholyan, NV, Kutsche, K & Meissner, G 2020, 'Single-channel properties of skeletal muscle ryanodine receptor pore Δ4923FF4924 in two brothers with a lethal form of fetal akinesia', Cell Calcium, vol. 87, 102182.
Ono, C, Fukuhara, T, Li, S, Wang, J, Sato, A, Izumi, T, Fauzyah, Y, Yamamoto, T, Morioka, Y, Dokholyan, NV, Standley, DM & Matsuura, Y 2020, 'Various miRNAs compensate the role of miR-122 on HCV replication', PLoS pathogens, vol. 16, no. 6 June, e1008308.


Chirasani, VR, Xu, L, Addis, HG, Pasek, DA, Dokholyan, NV, Meissner, G & Yamaguchi, N 2019, 'A central core disease mutation in the Ca2+-binding site of skeletal muscle ryanodine receptor impairs single-channel regulation', American Journal of Physiology - Cell Physiology, vol. 317, no. 2, pp. C358-C365.
Wodak, SJ, Paci, E, Dokholyan, NV, Berezovsky, IN, Horovitz, A, Li, J, Hilser, VJ, Bahar, I, Karanicolas, J, Stock, G, Hamm, P, Stote, RH, Eberhardt, J, Chebaro, Y, Dejaegere, A, Cecchini, M, Changeux, JP, Bolhuis, PG, Vreede, J, Faccioli, P, Orioli, S, Ravasio, R, Yan, L, Brito, C, Wyart, M, Gkeka, P, Rivalta, I, Palermo, G, McCammon, JA, Panecka-Hofman, J, Wade, RC, Di Pizio, A, Niv, MY, Nussinov, R, Tsai, CJ, Jang, H, Padhorny, D, Kozakov, D & McLeish, T 2019, 'Allostery in Its Many Disguises: From Theory to Applications', Structure, vol. 27, no. 4, pp. 566-578.
Sarker, M, Lee, HT, Mei, L, Krokhotin, A, de los Reyes, SE, Yen, L, Costantini, LM, Griffith, J, Dokholyan, NV, Alushin, GM & Campbell, SL 2019, 'Cardiomyopathy Mutations in Metavinculin Disrupt Regulation of Vinculin-Induced F-Actin Assemblies', Journal of Molecular Biology, vol. 431, no. 8, pp. 1604-1618.
Krokhotin, A, Du, H, Hirabayashi, K, Popov, K, Kurokawa, T, Wan, X, Ferrone, S, Dotti, G & Dokholyan, NV 2019, 'Computationally Guided Design of Single-Chain Variable Fragment Improves Specificity of Chimeric Antigen Receptors', Molecular Therapy - Oncolytics, vol. 15, pp. 30-37.
Brodie, NI, Popov, KI, Petrotchenko, EV, Dokholyan, NV & Borchers, CH 2019, 'Conformational ensemble of native α-synuclein in solution as determined by short-distance crosslinking constraint-guided discrete molecular dynamics simulations', PLoS computational biology, vol. 15, no. 3, e1006859.
Krokhotin, A, Sarker, M, Sevilla, EA, Costantini, LM, Griffith, JD, Campbell, SL & Dokholyan, NV 2019, 'Distinct Binding Modes of Vinculin Isoforms Underlie Their Functional Differences', Structure, vol. 27, no. 10, pp. 1527-1536.e3.
Dagliyan, O, Dokholyan, NV & Hahn, KM 2019, 'Engineering proteins for allosteric control by light or ligands', Nature Protocols, vol. 14, no. 6, pp. 1863-1883.
Popov, KI, Makepeace, KAT, Petrotchenko, EV, Dokholyan, NV & Borchers, CH 2019, 'Insight into the Structure of the “Unstructured” Tau Protein', Structure, vol. 27, no. 11, pp. 1710-1715.e4.
Sapienza, PJ, Popov, KI, Mowrey, DD, Falk, BT, Dokholyan, N & Lee, AL 2019, 'Inter-Active Site Communication Mediated by the Dimer Interface β-Sheet in the Half-the-Sites Enzyme, Thymidylate Synthase', Biochemistry, vol. 58, no. 30, pp. 3302-3313.
Wang, J, Williams, B, Chirasani, VR, Krokhotin, A, Das, R & Dokholyan, NV 2019, 'Limits in accuracy and a strategy of RNA structure prediction using experimental information', Nucleic acids research, vol. 47, no. 11, pp. 5563-5572.
Jiang, Y, Zhang, Y, Leung, JY, Fan, C, Popov, KI, Su, S, Qian, J, Wang, X, Holtzhausen, A, Ubil, E, Xiang, Y, Davis, I, Dokholyan, NV, Wu, G, Perou, CM, Kim, WY, Earp, HS & Liu, P 2019, 'MERTK mediated novel site Akt phosphorylation alleviates SAV1 suppression', Nature communications, vol. 10, no. 1, 1515.
Wang, J & Dokholyan, N 2019, 'MedusaDock 2.0: Efficient and Accurate Protein-Ligand Docking with Constraints', Journal of Chemical Information and Modeling, vol. 59, no. 6, pp. 2509-2515.
Bonfanti, S, Lionetti, MC, Fumagalli, MR, Chirasani, VR, Tiana, G, Dokholyan, NV, Zapperi, S & La Porta, CAM 2019, 'Molecular mechanisms of heterogeneous oligomerization of huntingtin proteins', Scientific reports, vol. 9, no. 1, 7615.
Ke, W, Hong, E, Saito, RF, Rangel, MC, Wang, J, Viard, M, Richardson, M, Khisamutdinov, EF, Panigaj, M, Dokholyan, NV, Chammas, R, Dobrovolskaia, MA & Afonin, KA 2019, 'RNA-DNA fibers and polygons with controlled immunorecognition activate RNAi, FRET and transcriptional regulation of NF-κB in human cells', Nucleic acids research, vol. 47, no. 3, pp. 1350-1361.
Zhu, C, Dukhovlinova, E, Council, O, Ping, L, Faison, EM, Prabhu, SS, Potter, EL, Upton, SL, Yin, G, Fay, JM, Kincer, LP, Spielvogel, E, Campbell, SL, Benhabbour, SR, Ke, H, Swanstrom, R & Dokholyan, NV 2019, 'Rationally designed carbohydrate-occluded epitopes elicit HIV-1 Env-specific antibodies', Nature communications, vol. 10, no. 1, 948.
Zhu, C, Han, Q, Samoshkin, A, Convertino, M, Linton, A, Faison, EM, Ji, RR, Diatchenko, L & Dokholyan, NV 2019, 'Stabilization of μ-opioid receptor facilitates its cellular translocation and signaling', Proteins: Structure, Function and Bioinformatics, vol. 87, no. 10, pp. 878-884.
Reilley, DJ, Popov, KI, Dokholyan, NV & Alexandrova, AN 2019, 'Uncovered Dynamic Coupling Resolves the Ambiguous Mechanism of Phenylalanine Hydroxylase Oxygen Binding', Journal of Physical Chemistry B, vol. 123, no. 21, pp. 4534-4539.
Li, X, Deng, M, Petrucelli, AS, Zhu, C, Mo, J, Zhang, L, Tam, JW, Ariel, P, Zhao, B, Zhang, S, Ke, H, Li, P, Dokholyan, NV, Duncan, JA & Ting, JPY 2019, 'Viral DNA Binding to NLRC3, an Inhibitory Nucleic Acid Sensor, Unleashes STING, a Cyclic Dinucleotide Receptor that Activates Type I Interferon', Immunity, vol. 50, no. 3, pp. 591-599.e6.
Proctor, EA, Mowrey, DD & Dokholyan, NV 2019, 'β-Methylamino-L-alanine substitution of serine in SOD1 suggests a direct role in ALS etiology', PLoS computational biology, vol. 15, no. 7, e1007225.


Xu, L, Chirasani, VR, Carter, JS, Pasek, DA, Dokholyan, NV, Yamaguchi, N & Meissner, G 2018, 'Ca2-mediated activation of the skeletal-muscle ryanodine receptor ion channel', Journal of Biological Chemistry, vol. 293, no. 50, pp. 19501-19509.
Dagliyan, O, Krokhotin, A, Ozkan-Dagliyan, I, Deiters, A, Der, CJ, Hahn, KM & Dokholyan, NV 2018, 'Computational design of chemogenetic and optogenetic split proteins', Nature communications, vol. 9, no. 1, 4042.
Xu, L, Mowrey, DD, Chirasani, VR, Wang, Y, Pasek, DA, Dokholyan, NV & Meissner, G 2018, 'G4941K substitution in the pore-lining S6 helix of the skeletal muscle ryanodine receptor increases RyR1 sensitivity to ytosolic and luminal Ca2+', Journal of Biological Chemistry, vol. 293, no. 6, pp. 2015-2028.
Zhang, Y, Hashemi, M, Lv, Z, Williams, B, Popov, KI, Dokholyan, NV & Lyubchenko, YL 2018, 'High-speed atomic force microscopy reveals structural dynamics of α -synuclein monomers and dimers', Journal of Chemical Physics, vol. 148, no. 12, 123322.
Zhu, C, Beck, MV, Griffith, JD, Deshmukh, M & Dokholyan, NV 2018, 'Large SOD1 aggregates, unlike trimeric SOD1, do not impact cell viability in a model of amyotrophic lateral sclerosis', Proceedings of the National Academy of Sciences of the United States of America, vol. 115, no. 18, pp. 4661-4665.
Wang, C, Aleksandrov, AA, Yang, Z, Forouhar, F, Proctor, EA, Kota, P, An, J, Kaplan, A, Khazanov, N, Boël, G, Stockwell, BR, Senderowitz, H, Dokholyan, NV, Riordan, JR, Brouillette, CG & Hunt, JF 2018, 'Ligand binding to a remote site thermodynamically corrects the F508del mutation in the human cystic fibrosis transmembrane conductance regulator', Journal of Biological Chemistry, vol. 293, no. 46, pp. 17685-17704.
Shobair, M, Popov, KI, Dang, YL, He, H, Jackson Stutts, M & Dokholyan, NV 2018, 'Mapping allosteric linkage to channel gating by extracellular domains in the human epithelial sodium channel', Journal of Biological Chemistry, vol. 293, no. 10, pp. 3675-3684.
Cloer, EW, Siesser, PF, Cousins, EM, Goldfarb, D, Mowrey, DD, Harrison, JS, Weir, SJ, Dokholyan, NV & Major, MB 2018, 'P62-dependent phase separation of patient-derived KEap1 mutations and Nrf2', Molecular and cellular biology, vol. 38, no. 22, e0064417.
Rackley, L, Stewart, JM, Salotti, J, Krokhotin, A, Shah, A, Halman, JR, Juneja, R, Smollett, J, Lee, L, Roark, K, Viard, M, Tarannum, M, Vivero-Escoto, J, Johnson, PF, Dobrovolskaia, MA, Dokholyan, NV, Franco, E & Afonin, KA 2018, 'RNA Fibers as Optimized Nanoscaffolds for siRNA Coordination and Reduced Immunological Recognition', Advanced Functional Materials, vol. 28, no. 48, 1805959.
Luo, J, Samanta, S, Convertino, M, Dokholyan, NV & Deiters, A 2018, 'Reversible and Tunable Photoswitching of Protein Function through Genetic Encoding of Azobenzene Amino Acids in Mammalian Cells', ChemBioChem, vol. 19, no. 20, pp. 2178-2185.
Kaur, G, Guruprasad, K, Temple, BRS, Shirvanyants, DG, Dokholyan, NV & Pati, PK 2018, 'Structural complexity and functional diversity of plant NADPH oxidases', Amino Acids, vol. 50, no. 1, pp. 79-94.
Li, B, Tunc-Ozdemir, M, Urano, D, Jia, H, Werth, EG, Mowrey, DD, Hicks, LM, Dokholyan, NV, Torres, MP & Jones, AM 2018, 'Tyrosine phosphorylation switching of a G protein', Journal of Biological Chemistry, vol. 293, no. 13, pp. 4752-4766.
Han, Q, Liu, D, Convertino, M, Wang, Z, Jiang, C, Kim, YH, Luo, X, Zhang, X, Nackley, A, Dokholyan, NV & Ji, RR 2018, 'miRNA-711 Binds and Activates TRPA1 Extracellularly to Evoke Acute and Chronic Pruritus', Neuron, vol. 99, no. 3, pp. 449-463.e6.


Thompson, PM, Ramachandran, S, Case, LB, Tolbert, CE, Tandon, A, Pershad, M, Dokholyan, NV, Waterman, CM & Campbell, SL 2017, 'A Structural Model for Vinculin Insertion into PIP2-Containing Membranes and the Effect of Insertion on Vinculin Activation and Localization', Structure, vol. 25, no. 2, pp. 264-275.
Woods, CT, Lackey, L, Williams, B, Dokholyan, NV, Gotz, D & Laederach, A 2017, 'Comparative Visualization of the RNA Suboptimal Conformational Ensemble In Vivo', Biophysical journal, vol. 113, no. 2, pp. 290-301.
Zhu, C, Mowrey, DD & Dokholyan, N 2017, Computational protein design through grafting and stabilization. in Methods in Molecular Biology. Methods in Molecular Biology, vol. 1529, Humana Press Inc., pp. 227-241.
Jacob, RB, Michaels, KC, Anderson, CJ, Fay, JM & Dokholyan, NV 2017, 'Corrigendum: Harnessing Nature's Diversity: Discovering organophosphate bioscavenger characteristics among low molecular weight proteins', Scientific reports, vol. 7, 46727, pp. 46727.
Krokhotin, A, Mustoe, AM, Weeks, KM & Dokholyan, NV 2017, 'Direct identification of base-paired RNA nucleotides by correlated chemical probing', RNA, vol. 23, no. 1, pp. 6-13.
Dagliyan, O, Karginov, AV, Yagishita, S, Gale, ME, Wang, H, Dermardirossian, C, Wells, CM, Dokholyan, NV, Kasai, H & Hahn, KM 2017, 'Engineering Pak1 Allosteric Switches', ACS Synthetic Biology, vol. 6, no. 7, pp. 1257-1262.
Mowrey, DD, Xu, L, Mei, Y, Pasek, DA, Meissner, G & Dokholyan, NV 2017, 'Ion-pulling simulations provide insights into the mechanisms of channel opening of the skeletal muscle ryanodine receptor', Journal of Biological Chemistry, vol. 292, no. 31, pp. 12947-12958.
Williams, B, Convertino, M, Das, J & Dokholyan, NV 2017, 'Molecular Mechanisms of the R61T Mutation in Apolipoprotein E4: A Dynamic Rescue', Biophysical journal, vol. 113, no. 10, pp. 2192-2198.
Mu, X, Choi, S, Lang, L, Mowray, D, Dokholyan, NV, Danielsson, J & Oliveberg, M 2017, 'Physicochemical code for quinary protein interactions in Escherichia coli', Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 23, pp. E4556-E4563.
Dakal, TC, Kala, D, Dhiman, G, Yadav, V, Krokhotin, A & Dokholyan, N 2017, 'Predicting the functional consequences of non-synonymous single nucleotide polymorphisms in IL8 gene', Scientific reports, vol. 7, no. 1, 6525.
Krokhotin, A & Dokholyan, NV 2017, 'Protein folding: Over half a century lasting quest: Comment on “There and back again: Two views on the protein folding puzzle” by Alexei V. Finkelstein et al.', Physics of Life Reviews, vol. 21, pp. 72-74.
Miao, Z, Adamiak, RW, Antczak, M, Batey, RT, Becka, AJ, Biesiada, M, Boniecki, MJ, Bujnicki, JM, Chen, SJ, Cheng, CY, Chou, FC, Ferré-D'Amaré, AR, Das, R, Dawson, WK, Ding, F, Dokholyan, NV, Dunin-Horkawicz, S, Geniesse, C, Kappel, K, Kladwang, W, Krokhotin, A, Łach, GE, Major, F, Mann, TH, Magnus, M, Pachulska-Wieczorek, K, Patel, DJ, Piccirilli, JA, Popenda, M, Purzycka, KJ, Ren, A, Rice, GM, Santalucia, J, Sarzynska, J, Szachniuk, M, Tandon, A, Trausch, JJ, Tian, S, Wang, J, Weeks, KM, Williams, B, Xiao, Y, Xu, X, Zhang, D, Zok, T & Westhof, E 2017, 'RNA-Puzzles Round III: 3D RNA structure prediction of five riboswitches and one ribozyme', RNA, vol. 23, no. 5, pp. 655-672.
Dronamraju, R, Ramachandran, S, Jha, DK, Adams, AT, Difiore, JV, Parra, MA, Dokholyan, NV & Strahl, BD 2017, 'Redundant Functions for Nap1 and Chz1 in H2A.Z Deposition', Scientific reports, vol. 7, no. 1, 10791.
Brodie, NI, Popov, KI, Petrotchenko, EV, Dokholyan, NV & Borchers, CH 2017, 'Solving protein structures using short-distance cross-linking constraints as a guide for discrete molecular dynamics simulations', Science Advances, vol. 3, no. 7, e1700479.
Williams, B, Zhao, B, Tandon, A, Ding, F, Weeks, KM, Zhang, Q & Dokholyan, NV 2017, 'Structure modeling of RNA using sparse NMR constraints', Nucleic acids research, vol. 45, no. 22, pp. 12638-12647.
Das, J, Aleksandrov, AA, Cui, L, He, L, Riordan, JR & Dokholyan, NV 2017, 'Transmembrane helical interactions in the CFTR channel pore', PLoS computational biology, vol. 13, no. 6, e1005594.

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