Design and characterization of a protein fold switching network

Abstract

AbstractProtein sequences encoding three common small folds (3α, β–grasp, and α/β–plait) were connected in a network with high-identity intersections, termed nodes. The structures of proteins around nodes were determined using NMR spectroscopy and analyzed for stability and binding function. To generate nodes, the amino acid sequence encoding a shorter fold (3a or β–grasp) is embedded in the structure of the~50% longer α/β–plait fold and a new sequence is designed that satisfies two sets of native interactions. This leads to protein pairs with a 3a or β–grasp fold in the shorter form but an α/β–plait fold in the longer form. Further, embedding smaller antagonistic folds in longer folds creates critical states in the longer folds such that single amino acid substitutions can switch both their fold and function. This suggests that abrupt fold switching may be a mechanism of evolving new protein structures and functions.