My lab studies the folding and design of proteins, enzymes, vaccine antigens, and biosensors. When I came here in 1999, I was a bioinformaticist and my lab worked exclusively in computational biology. Since then, we have evolved into a mostly experimental lab, with a little computation still mixed in. Our early work included algorithm development in protein structural bioinformatics, including structure prediction, contact map prediction, local structure prediction, hidden Markov models, sequence alignment, molecular surface area calculation, torsion space molecular dynamics, simplified representations for molecular dynamics, bioinformatics-driven force fields, structure-based alignment, and models for folding pathways. We proposed the "phone cord effect" to explain superhelicity in alpha helical crossovers.
Starting about ten years ago, we began doing experimental work on green fluorescent protein (GFP) with the help of molecular biologist Prof. Donna E. Crone. We created a non-circularly permuted "re-wired" GFP, a permuted and truncated "leave-one-out" GFP, a variant that folds faster and more efficiently, and a GFP-base biosensor. We inserted strategically-placed disulfides to test specific hypotheses for the folding pathway of GFP and reasoned out the presence of two specific folding intermediates. More recently we are studying the formation of the fluorescent chromophore and the dependence of GFP fluorescence on specific residues and on thermodynamic stability.
The principle thrust of the lab is to develop the leave-one-out (LOO) method for GFP-based biosensors. By combining computational design and high throughput screening, we find sets of mutations that complement a specific bound peptide and allow the truncated LOO-GFP to fold and glow only in the presence of a target protein which has been unfolded to expose that sequence. A biosensor for detection of H5N1 influenza virus hemagglutinin was published in 2015. We are collaborating on the development of a sensor for dengue virus and putting those sensors on protein fibers.
We are also engaged in a collaborative effort to develop a contraceptive vaccine. The vaccine will produce temporary and reversible infertility. Instead of having to take an action to be protected, you will be protected by default, and would need to take an action to be temporarilly fertile again. The vaccine targets the sperm-specific calcium channel CatSper, which is required for sperm hyperactive motility and therefore for fertility. Sperm antigens are placed on the surface of non-infectious virus-like particles (VLP) for vaccination.
A contraceptive vaccine is a humane way to deal with global overpopulation. Overpopulation is widely believed to be the root cause of anthropogenic climate change, overfishing, fresh water depletion, war, famine etc. -- in short, overpopulation is an existential threat. I recently published a computational model, called World4, for global population, predicting that a peak is coming soon. The good news is that by making every child a wanted child, population growth can be stopped humanely.
My lab is using chimeric constructs of Human Papilloma Virus (HPV) L1 protein as a self-assmbling virus-like nanoparticle. Theses particle raise strong immunity to epitopes on their surface. We are placing CatSper loops on the surface for a contracpetive vaccine, SARS-CoV2 spike protein loops on the surface as a glycan-free COVID vaccine, and metastatic cancer biomarkers for a late-stage cancer immunotherapeutic. This versatile chimeric-HPV technology has many applications in epitope-directed vaccine design.
This work was made possible by our collaborators, the Center for Computational Innovation (CCI), and Center for Biotechnology and Interdisciplinary Sciences (CBIS), and by grants from the NSF, NIH, Rosetta Commons, and a private foundation.
BA. Carleton College, Northfield MN.
Ph.D. University of California, San Diego
- Bystroff, C. (2021). Footprints to singularity: A global population model explains late 20th century slow-down and predicts peak within ten years. PloS one, 16(5).
- Hwang, J. Y., Nawaz, S., Choi, J., Wang, H., Hussain, S., Nawaz, M., ... & Chung, J. J. (2021). Genetic defects in DNAH2 underlie male infertility with multiple morphological abnormalities of the sperm flagella in humans and mice. Frontiers in cell and developmental biology, 9.
- Koehler Leman, J., Weitzner, B. D., Renfrew, P. D., Lewis, S. M., Moretti, R., Watkins, A. M., ... & Bonneau, R. (2020). Better together: Elements of successful scientific software development in a distributed collaborative community. PLoS computational biology, 16(5), e1007507.
- Leman, J. K., Weitzner, B. D., Lewis, S. M., Adolf-Bryfogle, J., Alam, N., Alford, R. F., ... & Bonneau, R. (2020). Macromolecular modeling and design in Rosetta: recent methods and frameworks. Nature methods, 17(7), 665-680.
- Booth, R., Churion, K., Bystroff, C., & Bondos, S. (2020). Binding, Release, and Detection of Ligands by Ultrabithorax Protein‐Based Materials. The FASEB Journal, 34(S1), 1-1.
- Kizer, M., Huntress, I. D., Walcott, B., Fraser, K., Bystroff, C., & Wang, X. (2019). The complex between a multi-crossover DNA nanostructure, PX-DNA, and T7 endonuclease I. Biochemistry. Mar 12;58(10):1332-1342.
- Bystroff, C. (2018). Intramembranal disulfide cross-linking elucidates the super-quaternary structure of mammalian CatSpers. Reproductive Biology, 18(1), 76-82.
- Hooper WF, Walcott BD, Wang X, Bystroff C. (2018) Fast design of arbitrary length loops in proteins using InteractiveRosetta. BMC Bioinformatics, 19(1), 337.
- Bystroff C (2018) Will an anti-sperm contraceptive vaccine gain public acceptance? Obstetrics and Gynecology Reports. Volume 2(3): 1-1. ISSN: 2515-2955
- Banerjee S, Schenkelberg CD, Jordan TB, Reimertz JM, Crone EE, Crone DE, & Bystroff C. (2017). Mispacking and the Fitness Landscape of the Green Fluorescent Protein Chromophore Milieu. Biochemistry, 56(5), 736-747.