Role of backbone strain in de novo design of complex α/β protein structures

Author:

Koga Nobuyasu,Koga RieORCID,Liu Gaohua,Castellanos Javier,Montelione Gaetano T.ORCID,Baker David

Abstract

AbstractWe previously elucidated principles for designing ideal proteins with completely consistent local and non-local interactions which have enabled the design of a wide range of new αβ-proteins with four or fewer β-strands. The principles relate local backbone structures to supersecondary-structure packing arrangements of α-helices and β-strands. Here, we test the generality of the principles by employing them to design larger proteins with five- and six- stranded β-sheets flanked by α-helices. The initial designs were monomeric in solution with high thermal stability, and the nuclear magnetic resonance (NMR) structure of one was close to the design model, but for two others the order of strands in the β-sheet was swapped. Investigation into the origins of this strand swapping suggested that the global structures of the design models were more strained than the NMR structures. We incorporated explicit consideration of global backbone strain into the design methodology, and succeeded in designing proteins with the intended unswapped strand arrangements. These results illustrate the value of experimental structure determination in guiding improvement of de novo design, and the importance of consistency between local, supersecondary, and global tertiary interactions in determining protein topology. The augmented set of principles should inform the design of larger functional proteins.

Funder

Howard Hughes Medical Institute

DOE | Advanced Research Projects Agency - Energy

United States Department of Defense | Defense Advanced Research Projects Agency

United States Department of Defense | Defense Threat Reduction Agency

Foundation for the National Institutes of Health

MEXT | Japan Society for the Promotion of Science

MEXT | Japan Science and Technology Agency

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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