Superfunneled Energy Landscape of Protein Evolution Unifies the Principles of Protein Evolution, Folding, and Design

Evolution is essential for shaping the biological functions. Darwin proposed the selection as the driving force for evolution upon mutations. While mutations are clear, the quantification of the selection force is still challenging. In this study, we identified and quantified both thermodynamic stability and kinetic accessibility as the selection forces for protein evolution. The protein evolution can be viewed and quantified as a trajectory moving along a superfunneled energy landscape with a line attractor at the bottom. The resulting evolved sequences and structures show strong protein characteristics including the hydrophobic core, high designability, and fast folding. The evolution principle uncovered here is validated on real proteins and sheds light on the protein design.