Protein Robustness Promotes Evolutionary Innovations on Large Evolutionary Time Scales

Recent laboratory experiments suggest that a molecule’s ability to evolve neutrally is important for its ability to generate evolutionary innovations. In contrast to laboratory experiments, life unfolds on time scales of billions of years. Here, we ask whether a molecule’s ability to evolve neutrally – a measure of its robustness – facilitates evolutionary innovation also on these large time scales. To this end, we use protein designability, the number of sequences that can adopt a given protein structure, as an estimate of the structure’s ability to evolve neutrally. Based on two complementary measures of functional diversity – catalytic diversity and molecular function diversity in gene ontology – we show that more robust proteins have a greater capacity to produce functional innovations. Significant associations among structural designability, folding rate, and intrinsic disorder also exist, underlining the complex relationship of the structural factors that affect protein evolution.