The Last Secret of Protein Folding: The Real Relationship Between Long-Range Interactions and Local Structures

The protein folding problem has been extensively studied for decades, and hundreds of thousands of protein structures have been solved. Yet, how proteins fold from a linear peptide chain to their unique 3D structures is not fully understood. With key clues having emerged unexpectedly from the field of nanoscience, a "Confined Lowest Energy Fragment" (CLEF) hypothesis was proposed. The CLEF hypothesis states that a protein chain can be divided into CLEFs, the semi-independent folding units, by a small number of key residues that form key long-range interactions. The native structure of a CLEF is the lowest energy state under the constraints of the key long-range interactions, but the native structure of the whole protein is not necessary the lowest energy state as Anfinsen's thermodynamic hypothesis suggested. The CLEF hypothesis proposes a unified CLEF mechanism for protein folding, basically a two-step process. In the first step, the favorable enthalpy of CLEFs for native structures quickly brings those residues for the key long-range interactions together, forming intermediates corresponding to the so-called hydrophobic collapse. In the second step, those collapsed key residues shuffle for the right combination to form the native key long-range interactions. The CLEF hypothesis provides a simple solution to all protein folding paradoxes, and proposes a "CLEF Age" or "Stone Age" for the prebiotic evolution of proteins.