Department of Biological Chemistry
Faculty of Biochemistry
Weizmann Institute of Science
Rehovot 76100, Israel
- Computational design and experimental characterization of novel protein function
- Design principles of molecular recognition in antibodies and enzymes
- Molecular recognition and design of interactions in biological membranes
New: Congratulations to Christoffer Norn for being awarded the prestigious Boehringer Ingelheim doctoral fellowship!
New: Read our Perspective on biomolecular design and structure determination: Cell 149: 262
The incredible diversity of life depends on precise molecular recognition between biological macromolecules. How do proteins tightly bind their targets and not the thousands of different macromolecules that coexist in the cell? This is a fundamental issue that could impact our ability to rationally design diagnostics, therapeutics, and enzymes not seen in nature. It is also a fascinating problem considering that the amino acid building blocks of proteins largely lack the hallmark features of fine recognition encoded, for instance, in nucleic acid hydrogen-bonding patterns. A remarkable example of the potency and importance of molecular recognition is illustrated by the immune system, which can generate a virtually limitless antibody response to recognize and often disable pathogens that neither the organism nor its ancestors ever encountered. Recent progress has made it possible to address this and a wide spectrum of related questions through computational design, where amino acids on protein surfaces are sculpted to effect new, predetermined functions. The vast number of combinations of sequence and conformational alternatives are computationally evaluated, and promising candidates are experimentally tested to refine our understanding of molecular recognition. We recently used these capabilities in order to computationally design novel proteins that bind and block influenza hemagglutinin infection (Science 332: 816, Nature Biotech. 30: 543), and these proteins are now investigated for their therapeutic potential.
Our research is at the interface of cellular biology, biophysics, and evolution. We use and develop methods for computational protein design within the framework of the state-of-the-art Rosetta software for macromolecular modeling. We then use in vitro evolution and selection for binding, biophysical binding experiments, and crystallization to test, refine, and gather new information on molecular recognition. The methods we develop can also be used to design new classes of protein inhibitors, diagnostics, and molecular probes not seen in nature, and may in future be the basis for design of therapeutics.
The deep connections between (left-to-right) molecular phenomena in biology, computation, thermodynamics, and applications. De novo design has made important progress on some of these problems (e.g., fold design, functional site design), but the majority of the challenges remain unmet. By generating new biological macromolecules with desired properties de novo design promises to shed new light on the essential features of biological activities and to produce molecules with potential uses in research, industry, and biomedicine. Taken from Fleishman & Baker Cell 149:262.
Funding: We are grateful for funding from the Israel Science Foundation, the European Research Council, a Marie Curie Reintegration Grant, a career development award from the Human Frontier Science Program, an Alon Fellowship, the Geffen Fund, the Yeda-Sela Center, the Reich Family Foundation, and a donation from Sam Switzer and Family. The lab is a member of the Israel Science Foundation's I-CORE Center of Excellence in Structural Cell Biology.