TY - JOUR
T1 - Hotspot-centric de novo design of protein binders
AU - Fleishman, Sarel J.
AU - Corn, Jacob E.
AU - Strauch, Eva Maria
AU - Whitehead, Timothy A.
AU - Karanicolas, John
AU - Baker, David
N1 - Funding Information:
We thank Ingemar Andre for many insights and Rickard Hedman for help with computations of lysozyme and its associated antibody. We thank Dina Schneidman-Duhovny and Haim Wolfson for suggestions and for providing source code for manipulating PatchDock results. Computations were carried out on computational resources generously provided by participants in Rosetta@Home and the Argonne Leadership Computing Facility. We thank Darwin O. V. Alonso and Keith E. Leidig for their support and maintenance of the computational infrastructure in the Baker laboratory. S.J.F. was supported by a long-term fellowship from the Human Frontier Science Program . J.E.C. was supported by the Jane Coffin Childs Memorial Fund . E.-M.S. was supported by a career development award from the Northwest Regional Center of Excellence National Institutes of Health/National Institute of Allergy and Infectious Diseases AI057141 . This research was supported by the Protein Design Processes grant from the Defense Advanced Research Program Agency , the Defense Threat Reduction Agency , the National Institutes of Health Yeast Resource Center , and the Howard Hughes Medical Institute .
PY - 2011/11/11
Y1 - 2011/11/11
N2 - 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.
AB - 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.
KW - antibody engineering
KW - computational design
KW - conformational plasticity
KW - negative design
KW - protein interactions
UR - http://www.scopus.com/inward/record.url?scp=80855140813&partnerID=8YFLogxK
U2 - 10.1016/j.jmb.2011.09.001
DO - 10.1016/j.jmb.2011.09.001
M3 - Article
C2 - 21945116
AN - SCOPUS:80855140813
SN - 0022-2836
VL - 413
SP - 1047
EP - 1062
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
IS - 5
ER -