Acta Physico-Chimica Sinica ›› 2020, Vol. 36 ›› Issue (1): 1907002.doi: 10.3866/PKU.WHXB201907002

Special Issue: Special Issue in Honor of Academician Youqi Tang on the Occasion of His 100th Birthday

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"Confined Lowest Energy Structure Fragments (CLESFs)" Hypothesis for Protein Structure and the "Stone Age" of Protein Prebiotic Evolution

Aoneng Cao*()   

  • Received:2019-07-01 Accepted:2019-08-22 Published:2019-09-02
  • Contact: Aoneng Cao
  • Supported by:
    the National Natural Science Foundation of China(31871007);the National Natural Science Foundation of China(31571024);the National Key Research and Development Plan of China(2016YFA0201600)


The protein folding problem is regarded as the second genetic code which has yet to be deciphered. To date, Anfinsen's thermodynamic hypothesis, i.e., the native structure of a protein is its most stable state, is the only generally accepted theory for protein folding, although exceptions have been reported. However, this hypothesis is a simple overall statement, with no information regarding where or how a protein is folded. The mechanism underlying protein folding has not yet been elucidated, and it is still not clear how the overall sequence (context) determines the structure of a protein. Based on our recent study, we propose a "Confined Lowest Energy Structure Fragments" (CLESFs) hypothesis. This hypothesis states that proteins are CLESFs joined together by a small number of strong constraints (key long-range interactions). Although the native structure of a protein contains various long-range interactions between amino acids that are far apart in the sequence, only a few strong interactions, such as disulfide bonds, hydrophobic packing, structural ion coordination as in zinc fingers, and hydrogen-bonding networks within beta-sheets, are critical. These key long-range interactions serve as a form of punctuation in the "language" of protein sequence and divide the protein sequence into different "sentences, " i.e., fragments (CLESFs). The local native structures of these CLESFs are the lowest energy structures under the confinements of those key long-range interactions, but the overall protein structure is not necessarily the global minimum as Anfinsen hypothesized. The same fragment may adopt different native structures in different proteins. Each native structure of the same fragment in a different protein is a local minimum for the free fragment and the "global minimum" for the fragment under the specific confinement in the specific protein. Essentially, the native local structures of the CLESFs have an enthalpic advantage (local minimum) which serves as a driving force to form the key long-range interactions; the key long-range interactions stabilize the native local structures with entropy effects by excluding enormous amount of random conformations possible for the fragments. Our CLESFs hypothesis suggests that the protein folding code is not as mysterious as previously thought. Only a few critical long-range interactions have principal influence on the local structures of protein fragments. This is why protein fragments can be grafted onto different proteins, and even more notably, can be grafted onto gold nanoparticles to form a "goldbody". Given that short peptides are generally flexible, and flexible peptides are usually unstable and inactive, it is still a mystery how proteins, i.e., peptides that are long enough to fold into unique structures, evolved in the first place. The CLESFs hypothesis implies that prior to the appearance of the first protein that was long enough to fold into a unique stable structure, there might have been a "Stone Age" during prebiotic protein evolution. At that time, short peptides that could not fold by themselves might have been able to adopt active conformations with a few strong anchors to the surface of "stones", such as rocks, solid particles, or vesicles in the primitive soup, forming CLESFs and gaining an evolutionary advantage against degradation. Later, multiple CLESFs on the same "stone" might have assembled in certain ways to perform more complicated functions, and finally, the first protein might have emerged when individual CLESFs joined together and left the "stone".

Key words: Protein folding, Peptide, Prebiotic, Hybrid, Artificial protein, Goldbody


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