Structure-based design of supercharged, highly thermoresistant antibodies

Aleksandr E. Miklos, Christien Kluwe, Bryan S. Der, Supriya Pai, Aroop Sircar, Randall A. Hughes, Monica Berrondo, Jianqing Xu, Vlad Codrea, Patricia E. Buckley, Alena M. Calm, Heather S. Welsh, Candice R. Warner, Melody A. Zacharko, James P. Carney, Jeffrey J. Gray, George Georgiou, Brian Kuhlman, Andrew D. Ellington

Research output: Contribution to journalArticlepeer-review

Abstract

Mutation of surface residues to charged amino acids increases resistance to aggregation and can enable reversible unfolding. We have developed a protocol using the Rosetta computational design package that "supercharges" proteins while considering the energetic implications of each mutation. Using a homology model, a single-chain variable fragment antibody was designed that has a markedly enhanced resistance to thermal inactivation and displays an unanticipated ≈30-fold improvement in affinity. Such supercharged antibodies should prove useful for assays in resource-limited settings and for developing reagents with improved shelf lives.

Original languageEnglish (US)
Pages (from-to)449-455
Number of pages7
JournalChemistry and Biology
Volume19
Issue number4
DOIs
StatePublished - Apr 20 2012

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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