Hi! I'm Mark, a research assistant professor at TTIC working on protein and drug design algorithms. I've been interested in protein design since the tenth grade, when I made a paper model of an enzyme (a ribonuclease) to see if I could figure out what mutations would make it specific to digest viral RNA. I realized soon that much more sophisticated techniques were needed, and as a graduate student in Bruce Donald's lab at Duke University, I began working on such techniques. The field has already made a lot of progress, and I think I've made some significant contributions (see below). But there is still a significant gap between the model of reality that we currently use in our designs, and the actual reality dictated by the laws of physics that determines how proteins and drugs behave in nature. Closing this gap would let us design molecules like an architect designs buildings—we will know ahead of time how they will work in real life. Builders building a skyscraper don't expect their first several tries to fall down, and we shouldn't have to expect that for drug design either. I think we can learn to design proteins and drugs in a similarly systematic way, even for fairly complicated functions.

Some algorithms I have developed toward this goal:
EPIC (Energy as Polynomials in Internal Coordinates)
DEEPer (Dead-End Elimination with Perturbations)
COMETS (Constrained Optimization of Multistate Energies by Tree Search)
LUTE (Local Unpruned Tuple Expansion)

I have implemented all these algorithms as part of OSPREY, the Donald lab's open-source protein design software package.

During my research in graduate school, I have come to believe that the difficulty of accurately and efficiently estimating conformational energies is one of the biggest barriers, if not the biggest, to the widespread practical use of our algorithms. So as I begin my independent research, my biggest priority is to develop design techniques that address this difficulty: either by incorporating more accurate energy modeling (as I've tried to do in some of my thesis work), or by relying less on quantitative energy estimation when making predictions.


  1. Hallen, Mark A., Jonathan D. Jou, and Bruce R. Donald. "LUTE (Local Unpruned Tuple Expansion): Accurate continuously flexible protein design with general energy functions and rigid-rotamer-like efficiency." Research in Computational Molecular Biology (RECOMB) 2016 proceedings, volume 9649 of Lecture Notes in Computer Science, pp. 122-136. Springer International Publishing, 2016.
  2. Pan, Yuchao, Yuxi Dong, Jingtian Zhou, Mark Hallen, Bruce R. Donald, Jianyang Zeng, and Wei Xu. "cOSPREY: A cloud-based distributed algorithm for large-scale computational protein design." Journal of Computational Biology 2016;23(9):737-749.
  3. Hallen, Mark A., Pablo Gainza, and Bruce R. Donald. "Compact representation of continuous energy surfaces for more efficient protein design." Journal of Chemical Theory and Computation 2015;11(5):2292-2306.
  4. Hallen, Mark A. and Bruce R. Donald. "COMETS (Constrained Optimization of Multistate Energies by Tree Search): A provable and efficient algorithm to optimize binding affinity and specificity with respect to sequence." Research in Computational Molecular Biology (RECOMB) 2015 proceedings, volume 9029 of Lecture Notes in Computer Science, pp. 122-135. Springer International Publishing, 2015.
    Journal version: Hallen, Mark A. and Bruce R. Donald. "COMETS (Constrained Optimization of Multistate Energies by Tree Search): A provable and efficient protein design algorithm to optimize binding affinity and specificity with respect to sequence." Journal of Computational Biology 2016;23(5):311-321.
  5. Kwon, Young Do, Marie Pancera, Priyamvada Acharya, Ivelin S. Georgiev, Emma T. Crooks, Jason Gorman, M. Gordon Joyce, Miklos Guttman, Xiaochu Ma, Sandeep Narpala, Cinque Soto, Daniel S. Terry, Yongping Yang, Tongqing Zhou, Goran Ahlsen, Robert T. Bailer, Michael Chambers, Gwo-Yu Chuang, Nicole A. Doria-Rose, Aliaksandr Druz, Mark A. Hallen, Adam Harned, Tatsiana Kirys, Mark K. Louder, Sijy O’Dell, Gilad Ofek, Keiko Osawa, Madhu Prabhakaran, Mallika Sastry, Guillaume B. E. Stewart-Jones, Jonathan Stuckey, Paul V. Thomas, Tishina Tittley, Constance Williams, Baoshan Zhang, Hong Zhao, Zhou Zhou, Bruce R. Donald, Lawrence K. Lee, Susan Zolla-Pazner, Ulrich Baxa, Arne Schön, Ernesto Freire, Lawrence Shapiro, Kelly K. Lee, James Arthos, James B. Munro, Scott C. Blanchard, Walter Mothes, James M. Binley, Adrian B. McDermott, John R. Mascola, and Peter D. Kwong. "Crystal structure, conformational fixation and entry-related interactions of mature ligand-free HIV-1 Env." Nature Structural and Molecular Biology 2015;22:522-531.
  6. Roberts, Kyle E., Pablo Gainza, Mark A. Hallen, and Bruce R. Donald. "Fast gap-free enumeration of conformations and sequences for protein design." Proteins 2015;83(10):1859-1877.
  7. Hallen, Mark A., Daniel A. Keedy, and Bruce R. Donald. "Dead-End Elimination with Perturbations (‘DEEPer’): A provable protein design algorithm with continuous sidechain and backbone flexibility." Proteins 2013;81(1):18-39.
  8. Liu, Hong-Lei, Mark A. Hallen, and Sharyn A. Endow. "Altered nucleotide- microtubule coupling and increased mechanical output by a kinesin mutant." PLoS ONE 2012;7(10):e47148.
  9. Endow, Sharyn A. and Mark A. Hallen. "Anastral spindle assembly and γ-tubulin in Drosophila oocytes." BMC Cell Biol. 2011;12:1, doi: 10.1186/1471-2121-12-1.
  10. Hallen, Mark A., Zhang-Yi Liang, and Sharyn A. Endow. "Two-state displacement by the kinesin-14 Ncd stalk." Biophys. Chem. 2011;154(2-3):56-65, doi:10.1016/j.bpc.2011.01.001.
  11. Xu, Ying, Irene N. Falk, Mark A. Hallen, and Michael C. Fitzgerald. "Mass spectrometry- and lysine amidination-based protocol for thermodynamic analysis of protein folding and ligand binding interactions." Anal. Chem. 2011;83(9):3555-3562.
  12. Hallen, Mark, Bochong Li, Yu Tanouchi, Cheemeng Tan, Mike West, and Lingchong You. "Computation of steady-state probability distributions in stochastic models of cellular networks." PLoS Comp. Biol. 2011;7(10):e1002209.
  13. Hallen, Mark A., and Anita T. Layton. "Expanding the scope of quantitative FRAP analysis." J. Theor. Biol. 2010;262(2):295-305.
  14. Liang, Zhang-Yi, Mark A. Hallen, and Sharyn A. Endow. "Mature Drosophila meiosis I spindles comprise microtubules of mixed polarity." Curr. Biol. 2009;19(2):163-168.
  15. Hallen, Mark A., and Sharyn A. Endow. "Anastral spindle assembly: a mathematical model." Biophys. J. 2009;97(8):2191-2201.
  16. Hallen, Mark A. and Hans D. Hallen. "Synthesis of carboxylic acid monolayers by ozonolysis of 10-undecenyltrichlorosilane SAMs." J. Phys. Chem. C 2008;112(6):2086- 2090.
  17. Hallen, Mark A., Jianghai Ho, Christine D. Yankel, and Sharyn A. Endow. "Fluorescence recovery kinetic analysis of γ-tubulin binding to the mitotic spindle." Biophys. J. 2008;95(6):3048-3058.
  18. Hallen, Mark A., Zhang-Yi Liang, and Sharyn A. Endow. "Ncd motor binding and transport in the spindle." J. Cell Sci. 2008;121:3834-3841.
  19. Zou, Jianwei, Mark A. Hallen, Christine D. Yankel, and Sharyn A. Endow. "A microtubule-destabilizing kinesin motor regulates spindle length and anchoring in oocytes." J. Cell Biol. 2008;183(3):459-466.