The Last Secret of Protein Folding: The Real Relationship Between Long-Range Interactions and Local Structures
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The Last Secret of Protein Folding: The Real Relationship Between Long‑Range Interactions and Local Structures Aoneng Cao1 Accepted: 3 October 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
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. Keywords Protein folding · Levinthal’s paradox · Long-range interaction · Protein evolution · CLEF hypothesis · CLEF age
1 Introduction Proteins are the major performers of most sophisticated biological functions essential for all life on earth. And all those sophisticated biological functions are dependent on the unique three-dimensional structures of proteins. Only when the one-dimensional amino acid chain of a protein is folded into a specific three-dimensional structure, can the protein have biological activity. So the problem of protein folding is also called the second half of genetic code [1]. It has been an attractive goal to find a protein sequencestructure relationship as simple as the DNA genetic codon. One-dimensional DNA can simply correspond to onedimensional amino acid sequence, but it is not so simple or even impossible to match the one-dimensional amino acid sequence with the three-dimensional protein structure. Long before the first protein structure was solved, Pauling * Aoneng Cao [email protected] 1
Institute of Nanochemistry and Nanobiology, Shanghai University, Shanghai 200444, China
and his collaborators theoretically predicted the existence of the local secondary structures, viz., α-helix and β-sheet [2, 3]. However, Pauling’s work is mainly based on the main protein chain, without considering the side chain of amino acids, that is, there is no
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