The road less traveled in protein folding: evidence for multiple pathways

Free Energy Landscape theory of Protein Folding, introduced over 20 years ago, implies that a protein has many paths to the folded conformation with the lowest free energy. Despite the knowledge in principle, it has been remarkably hard to detect such pathways. The lack of such observations is primarily due to the fact that no one experimental technique can detect many parts of the protein simultaneously with the time resolution necessary to see such differences in paths. However, recent technical developments and employment of multiple experimental probes and folding prompts have illuminated multiple folding pathways in a number of proteins that had all previously been described with a single path.