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

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Abstract

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.

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Acknowledgements

I had the privilege of working as a postdoc in Professor Harold Scheraga’s lab at Cornell University during 1998–2000, and Harold’s unswerving devotion to science and rigorous handling of research have a major influence on my career. This work was supported by the Natural Science Foundation of China (Nos. 31871007, 22071145 and 31571024) and the National Basic Research Plan of China (2016YFA0201600).

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    Aoneng Cao

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Cao, A. The Last Secret of Protein Folding: The Real Relationship Between Long-Range Interactions and Local Structures. Protein J 39, 422–433 (2020). https://doi.org/10.1007/s10930-020-09925-w

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