Douglas Theobald

Associate Professor of Biochemistry

Departments/Programs

Biochemistry

Degrees

University of Colorado at Boulder, Ph.D.
University of Tennessee, B.S.

Expertise

Likelihood and Bayesian methods in structural bioinformatics and single molecule biochemistry.

Evolution of macromolecular structures and assemblies.

Evolution of membrane protein structure and function.

Profile

The goal of my research is to understand with atomic precision how macromolecules evolve novel structures, complexes, mechanisms, and functions. We characterize the specific dynamic pathways taken by enzymes during their evolution, by resurrecting entire lineages of ancestral enzymes along multiple evolutionary pathways. We analyze their functions and mechanisms biochemically, and determine their crystal structures in order to view a “stop-action movie” of their evolutionary progression. This work is highly interdisciplinary, relying on X-ray crystallography, enzymology, phylogenetics, bioinformatics, and population genetics. Webpage

Courses Taught

BCBP	200b	Reading in Macromolecular Structure-Function Analysis
BCHM	104a	Classical and Statistical Thermodynamics
BCHM	145a	How to Decide: Bayesian Inference and Computational Statistics

Awards and Honors

VELUX Visiting Professor, University of Copenhagen (2015 - 2016)

Alberta Gotthardt Strage and Henry Strage Award (2011 - 2012)

Camille and Henry Dreyfus New Faculty Award (2007)

American Cancer Society Postdoctoral Fellow (2004 - 2007)

Scholarship

Lys Sanz Moreta, Ahmad Salim Al-Sibahi, Douglas Theobald, William Bullock, Basile Nicolas Rommes, Andreas Manoukian, Thomas Hamelryck. "A Probabilistic Programming Approach to Protein Structure Superposition." 2019 IEEE Conference on Computational Intelligence in Bioinformatics and Computational Biology (CIBCB), 2019.

Jacob D. Wirth, Jeffrey I. Boucher, Joseph R. Jacobowitz, Scott Classen, and Douglas L. Theobald. "Functional and structural resilience of the substrate loop in the evolution of Plasmodium lactate dehydrogenase." Biochemistry 57. 45 (2018): 6434-6442.

Nguyen V, Wilson C, Homberger M, Stiller J, Agafonov R, Kutter S, English J, Theobald DL, Kern D. "Evolutionary drivers of thermoadaptation in enzyme catalysis." Science 355. 6322 (2017): 289-294.

Theobald, Douglas L.. "Purification and characterization of RhoPDE, a retinylidene/phosphodiesterase fusion protein and potential optogenetics tool from the choanoflagellate Salpingoeca rosetta.." Biochemistry 56. 43 (2017): 5812-5822.

Trieu MM, Devine EL, Lamarche LB, Ammerman AE, Greco JA, Birge RR, Theobald DL, Oprian DD. "Expression, Purification, and Spectral Tuning of RhoGC, a Retinylidene/Guanylyl Cyclase Fusion Protein and Optogenetics Tool from the Aquatic Fungus Blastocladiella emersonii.." J Biol Chem (2017).

Devine EL, Theobald DL, and Oprian DD. "Relocating the active-site lysine in rhodopsin: 2. Evolutionary intermediates." Biochemistry 55. 34 (2016): 4864-4870.

Steindel PA, Chen E, Wirth JD, and Theobald DL. "Gradual neofunctionalization in the convergent evolution of trichomonad lactate and malate dehydrogenases." Protein Science 25. 7 (2016): 1319-1331.

Theobald DL. "Presenilin adopts the ClC channel fold." Protein Science 25. 7 (2016): 1363-1365.

Chris Wilson, Roman Agafonov, Marc Hömberger, Steffen Kutter, Adelajda Zorba, Jackson Halpin, Vanessa Buosi, Renee Otten, David Waterman, Douglas L. Theobald, and Dorothee Kern. "Using ancient protein kinases to unravel a modern cancer drug’s mechanism." Science 347. 6224 (2015): 882–886.

Thomas Hamelryck, Wouter Boomsma, Jesper Ferkinghoff-Borg, Jes Frellsen, John Haslett, John T. Kent, Kanti V. Mardia, and Douglas L. Theobald. "Proteins, physics, and probabilities: An outline of a Bayesian formulation of the protein folding problem." Geometry Driven Statistics. Ed. John T. Kent and Ian Dryden. Chichester: John Wiley and Sons, 2015. 356-376.

Boucher JI, Jacobowitz JR, Beckett BC, Classen S, Theobald DL.. "An atomic-resolution view of neofunctionalization in the evolution of apicomplexan lactate dehydrogenases.." eLife 2014;10.7554/eLife.02304. (2014).

Mackin K, Roy R, and Theobald DL. "An empirical test of convergent evolution in rhodopsins." Molecular Biology and Evolution 31. 1 (2014): 85-95.

Devine EL, Oprian DD, and Theobald DL. "Relocating the active-site lysine in rhodopsin and implications for evolution of the retinylidene proteins." PNAS 110. 33 (2013): 13351-13355.

Lyumkis D, Brilot A, Theobald DL, and Grigorieff N. "Likelihood-based classification of cryo-EM images using FREALIGN." Journal of Structural Biology 183. 3 (2013): 377-388.

Mardia KV, Fallaize CJ, Barber S, Jackson RM, and Theobald DL. "Bayesian alignment of similarity shapes." The Annals of Applied Statistics 7. 2 (2013): 989-1009.

Ni L, Bronk P, Chang EC, Lowell AM, Flam JO, Panzano VC, Theobald DL, Griffith LC, Garrity PA. "A gustatory receptor paralogue controls rapid warmth avoidance in Drosophila." Nature 500. 7464 (2013): 580-584.

Theobald DL and Steindel PA. "Optimal simultaneous superpositioning of multiple structures with missing data." Bioinformatics 28. 15 (2012): 1972-1979.

Theobald DL. "Likelihood and empirical Bayes superpositions of multiple macromolecular structures." Bayesian methods in structural bioinformatics. Ed. Hamelryck T, Mardia KV, and Ferkinghoff-Borg J. New York: Springer Verlag, 2012

Piasta K, Theobald DL and Miller C. "Potassium-selective block of barium permeation through single KcsA channels." Journal of General Physiology 138. 4 (2011): 421-436.

Theobald DL. "On universal common ancestry, sequence similarity, and phylogenetic structure: The sins of P-values and the virtues of Bayesian evidence." Biology Direct 6. (2011): 60.

Theobald DL. Full Bayesian analysis of the generalized non-isotropic Procrustes problem with scaling. Proc. of 30th Leeds Annual Statistical Research (LASR) Workshop. Leeds, UK: Department of Statistics, University of Leeds, 2011.

Kang K, Pulver SR, Panzano VC, Chang EC, Griffith LC, Theobald DL and Garrity PA. "Analysis of Drosophila TRPA1 reveals an ancient origin for human chemical nociception." Nature 464. 7288 (2010): 597-600.

Liu P, Agrafiotis DK, and Theobald DL. "Fast determination of the optimal rotational matrix for macromolecular superpositions." Journal of Computational Chemistry 31. 7 (2010): 1561-1563.

Liu P, Agrafiotis DK, and Theobald DL. "Reply to comment on: 'Fast determination of the optimal rotational matrix for macromolecular superpositions'." Journal of Computational Chemistry Epub ahead of print. (2010).

Theobald DL and Miller C. "Membrane transport proteins: Surprises in structural sameness." Nature Structural & Molecular Biology 17. 1 (2010): 2-3.

Theobald DL. "A formal test of the theory of universal common ancestry." Nature 465. 7295 (2010): 219-222.

Theobald DL. "Dawkins' missing link." Rev. of The Greatest Show on Earth, by Dawkins, Richard. Reports of the National Center for Science Education vol. 30 May-June, 2010: 37-38.

Theobald DL. "Was the universal common ancestry proved? Reply." Nature 468. (2010): E10.

Theobald DL. A nonisotropic Bayesian approach to superpositioning multiple macromolecules.. Proc. of the 28th Leeds Annual Statistical Research (LASR) Workshop, "Statistical Tools for Challenges in Bioinformatics". University of Leeds, UK: 2009.

Theobald DL and Wuttke DS. "Accurate structural correlations from maximum likelihood superpositions." PLoS Computational Biology 4. 2 (2008): e43.

Theobald DL. "Punctuated equilibrium." International Encyclopedia of the Social Sciences. Second Edition ed. 1 vols. 2007.

Theobald DL and Wuttke DS. "Empirical Bayes hierarchical models for regularizing maximum likelihood estimation in the matrix Gaussian Procrustes problem." Proc Natl Acad Sci U S A 103. 49 (2006): 18521-7.

Theobald DL and Wuttke DS. "THESEUS: maximum likelihood superpositioning and analysis of macromolecular structures." Bioinformatics 22. 17 (2006): 2171-2.

Theobald DL and Wuttke DS. "Divergent evolution within protein superfolds inferred from profile-based phylogenetics." J Mol Biol 354. 3 (2005): 722-37.

Theobald DL. "Rapid calculation of RMSDs using a quaternion-based characteristic polynomial." Acta Crystallogr A 61. Pt 4 (2005): 478-80.

Mitton-Fry RM, Anderson EM, Theobald DL, Glustrom LW, and Wuttke DS. "Structural basis for telomeric single-stranded DNA recognition by yeast Cdc13." J Mol Biol 338. 2 (2004): 241-55.

Theobald DL and Wuttke DS. "Prediction of multiple tandem OB-fold domains in telomere end-binding proteins Pot1 and Cdc13." Structure 12. 10 (2004): 1877-9.

Theobald DL and Schultz SC. "Nucleotide shuffling and ssDNA recognition in Oxytricha nova telomere end-binding protein complexes." Embo J 22. 16 (2003): 4314-24.

Theobald DL, Cervantes RB, Lundblad V, and Wuttke DS. "Homology among telomeric end-protection proteins." Structure 11. 9 (2003): 1049-50.

Theobald DL, Mitton-Fry RM, and Wuttke DS. "Nucleic acid recognition by OB-fold proteins." Annual Review of Biophysics and Biomolecular Structure 32. (2003): 115-33.