Fleishman Lab

Laboratory of Protein Design


Proteins are responsible for all the molecular processes essential to life on Earth. But they are also incredibly complex molecules, and most mutations lead to their dysfunction. Our lab's mission is to understand how protein sequence and structure determine function and translate this understanding into practically useful computational tools for protein design. 

Our research combines computational methods development, including AI and atomistic modeling, and structural and biochemical wet-lab work. Our work probes protein design principles by computing new proteins and testing their activities in the lab. We are committed to making methods accessible to all scientists, and our algorithms have been used to optimize diverse antibodies, vaccines, therapeutic enzymes, and enzymes for green chemistry applications. We are proud that some of our designs have entered clinical and preclinical studies to treat severe medical conditions and to see protein design fuel the next wave of innovation in biotechnology and synthetic biology.

Research page

Selected Publications

Opportunities and challenges in design and optimization of protein function

Listov D., Goverde C. A., Correia B. E. & Fleishman S. J. (2024) Nature Reviews Molecular Cell Biology.

Computational optimization of antibody humanness and stability by systematic energy-based ranking

Tennenhouse A., Khmelnitsky L., Khalaila R., Yeshaya N., Noronha A., Lindzen M., Makowski E. K., Zaretsky I., Sirkis Y. F., Galon-Wolfenson Y., Tessier P. M., Abramson J., Yarden Y., Fass D. & Fleishman S. J. (2024) Nature Biomedical Engineering. 8, 1, p. 30-44

Designed active-site library reveals thousands of functional GFP variants

Weinstein J. Y., Martí-Gómez C., Lipsh-Sokolik R., Hoch S. Y., Liebermann D., Nevo R., Weissman H., Petrovich-Kopitman E., Margulies D., Ivankov D., McCandlish D. M. & Fleishman S. J. (2023) Nature Communications. 14, 2890.

Combinatorial assembly and design of enzymes

Lipsh-Sokolik R., Khersonsky O., Schröder S. P., de Boer C., Hoch S., Davies G. J., Overkleeft H. S. & Fleishman S. J. (2023) Science. 379, 6628, p. 195-201

Stable and Functionally Diverse Versatile Peroxidases Designed Directly from Sequences

Barber-Zucker S., Mindel V., Garcia-Ruiz E., Weinstein J. J., Alcalde M. & Fleishman S. J. (2022) Journal of the American Chemical Society. 144, 8, p. 3564-3571

De novo-designed transmembrane domains tune engineered receptor functions

Elazar A., Chandler N. J., Davey A. S., Weinstein J. Y., Nguyen J. V., Trenker R., Cross R. S., Jenkins M. R., Call M. J., Call M. E. & Fleishman S. J. (2022) eLife. 11, e75660.

Automated Design of Efficient and Functionally Diverse Enzyme Repertoires

Khersonsky O., Lipsh R., Avizemer Z., Ashani Y., Goldsmith M., Leader H., Dym O., Rogotner S., Trudeau D. L., Prilusky J., Amengual-Rigo P., Guallar V., Tawfik D. S. & Fleishman S. J. (2018) Molecular Cell. 72, 1, p. 178-186.e5

One-step design of a stable variant of the malaria invasion protein RH5 for use as a vaccine immunogen

Campeotto I., Goldenzweig A., Davey J., Barfod L., Marshall J. M., Silk S. E., Wright K. E., Draper S. J., Higgins M. K. & Fleishman S. J. (2017) Proceedings of the National Academy of Sciences of the United States of America. 114, 5, p. 998-1002

Automated Structure- and Sequence-Based Design of Proteins for High Bacterial Expression and Stability

Goldenzweig A., Goldsmith M., Hill S. E., Gertman O., Laurino P., Ashani Y., Dym O., Unger T., Albeck S., Prilusky J., Lieberman R. L., Aharoni A., Silman I., Sussman J., Tawfik D. & Fleishman S. J. (2016) Molecular Cell. 63, 2, p. 337-346
All Publications