Perturbing the energy landscape for improved packing during computational protein design.

Autor: Maguire JB; Program in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA., Haddox HK; Department of Biochemistry, University of Washington, Seattle, Washington, USA.; Institute for Protein Design, University of Washington, Seattle, Washington, USA., Strickland D; Department of Electrical and Computer Engineering, University of Washington, Seattle, Washington, USA., Halabiya SF; Department of Electrical and Computer Engineering, University of Washington, Seattle, Washington, USA., Coventry B; Institute for Protein Design, University of Washington, Seattle, Washington, USA.; Molecular Engineering PhD Program, University of Washington, Seattle, Washington, USA., Griffin JR; Department of Chemistry, State University of New York at Buffalo, Buffalo, New York, USA., Pulavarti SVSRK; Department of Chemistry, State University of New York at Buffalo, Buffalo, New York, USA., Cummins M; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA., Thieker DF; Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA., Klavins E; Department of Electrical and Computer Engineering, University of Washington, Seattle, Washington, USA., Szyperski T; Department of Chemistry, State University of New York at Buffalo, Buffalo, New York, USA., DiMaio F; Department of Biochemistry, University of Washington, Seattle, Washington, USA.; Institute for Protein Design, University of Washington, Seattle, Washington, USA., Baker D; Department of Biochemistry, University of Washington, Seattle, Washington, USA.; Institute for Protein Design, University of Washington, Seattle, Washington, USA.; Howard Hughes Medical Institute, University of Washington, Seattle, Washington, USA., Kuhlman B; Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Jazyk: angličtina
Zdroj: Proteins [Proteins] 2021 Apr; Vol. 89 (4), pp. 436-449. Date of Electronic Publication: 2020 Dec 11.
DOI: 10.1002/prot.26030
Abstrakt: 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.
(© 2020 Wiley Periodicals LLC.)
Databáze: MEDLINE
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