Hotspot-centric de novo design of protein binders

Sarel J. Fleishman, Jacob E. Corn, Eva Maria Strauch, Timothy A. Whitehead, John Karanicolas, David Baker

    Research output: Research - peer-reviewArticle

    • 23 Citations

    Abstract

    Protein-protein interactions play critical roles in biology, and computational design of interactions could be useful in a range of applications. We describe in detail a general approach to de novo design of protein interactions based on computed, energetically optimized interaction hotspots, which was recently used to produce high-affinity binders of influenza hemagglutinin. We present several alternative approaches to identify and build the key hotspot interactions within both core secondary structural elements and variable loop regions and evaluate the method's performance in natural-interface recapitulation. We show that the method generates binding surfaces that are more conformationally restricted than previous design methods, reducing opportunities for off-target interactions.

    LanguageEnglish (US)
    Pages1047-1062
    Number of pages16
    JournalJournal of Molecular Biology
    Volume413
    Issue number5
    DOIs
    StatePublished - Nov 11 2011

    Profile

    Proteins
    Hemagglutinins
    Computational Biology
    Human Influenza

    Keywords

    • antibody engineering
    • computational design
    • conformational plasticity
    • negative design
    • protein interactions

    ASJC Scopus subject areas

    • Molecular Biology

    Cite this

    Fleishman, S. J., Corn, J. E., Strauch, E. M., Whitehead, T. A., Karanicolas, J., & Baker, D. (2011). Hotspot-centric de novo design of protein binders. Journal of Molecular Biology, 413(5), 1047-1062. DOI: 10.1016/j.jmb.2011.09.001

    Hotspot-centric de novo design of protein binders. / Fleishman, Sarel J.; Corn, Jacob E.; Strauch, Eva Maria; Whitehead, Timothy A.; Karanicolas, John; Baker, David.

    In: Journal of Molecular Biology, Vol. 413, No. 5, 11.11.2011, p. 1047-1062.

    Research output: Research - peer-reviewArticle

    Fleishman, SJ, Corn, JE, Strauch, EM, Whitehead, TA, Karanicolas, J & Baker, D 2011, 'Hotspot-centric de novo design of protein binders' Journal of Molecular Biology, vol 413, no. 5, pp. 1047-1062. DOI: 10.1016/j.jmb.2011.09.001
    Fleishman SJ, Corn JE, Strauch EM, Whitehead TA, Karanicolas J, Baker D. Hotspot-centric de novo design of protein binders. Journal of Molecular Biology. 2011 Nov 11;413(5):1047-1062. Available from, DOI: 10.1016/j.jmb.2011.09.001
    Fleishman, Sarel J. ; Corn, Jacob E. ; Strauch, Eva Maria ; Whitehead, Timothy A. ; Karanicolas, John ; Baker, David. / Hotspot-centric de novo design of protein binders. In: Journal of Molecular Biology. 2011 ; Vol. 413, No. 5. pp. 1047-1062
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