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Perturbing the energy landscape for improved packing during computational protein design
  • +8
  • Jack Maguire,
  • Hugh Haddox,
  • Devin Strickland,
  • Samer Halabiya,
  • Brian Coventry,
  • Matthew Cummins,
  • David Thieker,
  • Eric Klavins,
  • Frank DiMaio,
  • David Baker,
  • Brian Kuhlman
Jack Maguire
University of North Carolina at Chapel Hill
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Hugh Haddox
University of Washington
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Devin Strickland
University of Washington
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Samer Halabiya
University of Washington
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Brian Coventry
University of Washington
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Matthew Cummins
University of North Carolina at Chapel Hill
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David Thieker
University of North Carolina at Chapel Hill
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Eric Klavins
University of Washington
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Frank DiMaio
University of Washington
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David Baker
University of Washington
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Brian Kuhlman
University of North Carolina at Chapel Hill
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Abstract

The FastDesign protocol in the molecular modeling program Rosetta iterates between sequence optimization and structure refinement to stabilize de novo designed protein structures and complexes. FastDesign has been used previously to design novel protein folds and assemblies with important applications in research and medicine. To promote sampling of alternative conformations and sequences, FastDesign includes stages where the energy landscape is smoothened by reducing repulsive forces. Here, we discover that this process disfavors larger amino acids in the protein core because the protein compresses in the early stages of refinement. By testing alternative ramping strategies for the repulsive weight, we arrive at a scheme that produces lower energy designs with more native-like sequence composition in the protein core. We further validate the protocol by designing and experimentally characterizing over 4000 proteins and show that the new protocol produces higher stability proteins.

Peer review status:IN REVISION

18 May 2020Submitted to PROTEINS: Structure, Function, and Bioinformatics
19 May 2020Assigned to Editor
19 May 2020Submission Checks Completed
11 Jun 2020Reviewer(s) Assigned
19 Jul 2020Review(s) Completed, Editorial Evaluation Pending
26 Aug 2020Editorial Decision: Revise Major