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: Contribution to journalArticle

  • 25 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: Contribution to journalArticle

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
@article{6cac02809df44886810814adf5bee4be,
title = "Hotspot-centric de novo design of protein binders",
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.",
keywords = "antibody engineering, computational design, conformational plasticity, negative design, protein interactions",
author = "Fleishman, {Sarel J.} and Corn, {Jacob E.} and Strauch, {Eva Maria} and Whitehead, {Timothy A.} and John Karanicolas and David Baker",
year = "2011",
month = "11",
day = "11",
doi = "10.1016/j.jmb.2011.09.001",
language = "English (US)",
volume = "413",
pages = "1047--1062",
journal = "Journal of Molecular Biology",
issn = "0022-2836",
publisher = "Academic Press Inc.",
number = "5",

}

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

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

UR - http://www.scopus.com/inward/citedby.url?scp=80855140813&partnerID=8YFLogxK

U2 - 10.1016/j.jmb.2011.09.001

DO - 10.1016/j.jmb.2011.09.001

M3 - Article

VL - 413

SP - 1047

EP - 1062

JO - Journal of Molecular Biology

T2 - Journal of Molecular Biology

JF - Journal of Molecular Biology

SN - 0022-2836

IS - 5

ER -