Design and characterization of a protein fold switching network

Biao Ruan, Yanan He, Yingwei Chen, Eun Jung Choi, Yihong Chen, Dana Motabar, Tsega Solomon, Richard Simmerman, Thomas Kauffman, D. Travis Gallagher, John Orban () and Philip N. Bryan ()
Additional contact information
Biao Ruan: Potomac Affinity Proteins
Yanan He: University of Maryland
Yingwei Chen: Potomac Affinity Proteins
Eun Jung Choi: Potomac Affinity Proteins
Yihong Chen: University of Maryland
Dana Motabar: Potomac Affinity Proteins
Tsega Solomon: University of Maryland
Richard Simmerman: Potomac Affinity Proteins
Thomas Kauffman: University of Maryland
D. Travis Gallagher: University of Maryland
John Orban: University of Maryland
Philip N. Bryan: Potomac Affinity Proteins

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract To better understand how amino acid sequence encodes protein structure, we engineered mutational pathways that connect three common folds (3α, β−grasp, and α/β−plait). The structures of proteins at high sequence-identity intersections in the pathways (nodes) were determined using NMR spectroscopy and analyzed for stability and function. To generate nodes, the amino acid sequence encoding a smaller fold is embedded in the structure of an ~50% larger fold and a new sequence compatible with two sets of native interactions is designed. This generates protein pairs with a 3α or β−grasp fold in the smaller form but an α/β−plait fold in the larger form. Further, embedding smaller antagonistic folds creates critical states in the larger folds such that single amino acid substitutions can switch both their fold and function. The results help explain the underlying ambiguity in the protein folding code and show that new protein structures can evolve via abrupt fold switching.

Date: 2023
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DOI: 10.1038/s41467-023-36065-3

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