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    Levinthal 1968

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    lagares869
    The document discusses potential pathways for protein folding based on three approaches. First, experiments with mutant alkaline phosphatase found temperature-sensitive folding steps. Second, computer modeling explored plausible folding sequences starting from the amino acid sequence. Third, computer modeling generated potential folding pathways for cytochrome C, myoglobin, and lysozyme by minimizing energy between segments and allowing manipulation of parts, though uniqueness was not proven. The document suggests protein folding may follow defined sequences of interactions rather than reaching the lowest energy state.

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    Levinthal 1968

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    lagares869
    98 views2 pages
    The document discusses potential pathways for protein folding based on three approaches. First, experiments with mutant alkaline phosphatase found temperature-sensitive folding steps. Second, computer modeling explored plausible folding sequences starting from the amino acid sequence. Third, computer modeling generated potential folding pathways for cytochrome C, myoglobin, and lysozyme by minimizing energy between segments and allowing manipulation of parts, though uniqueness was not proven. The document suggests protein folding may follow defined sequences of interactions rather than reaching the lowest energy state.

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    The document discusses potential pathways for protein folding based on three approaches. First, experiments with mutant alkaline phosphatase found temperature-sensitive folding steps. Second, computer modeling explored plausible folding sequences starting from the amino acid sequence. Third, computer modeling generated potential folding pathways for cytochrome C, myoglobin, and lysozyme by minimizing energy between segments and allowing manipulation of parts, though uniqueness was not proven. The document suggests protein folding may follow defined sequences of interactions rather than reaching the lowest energy state.

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    © All Rights Reserved
    Download as PDF, TXT or read online from Scribd
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    98 views2 pages

    Levinthal 1968

    Uploaded by

    lagares869
    The document discusses potential pathways for protein folding based on three approaches. First, experiments with mutant alkaline phosphatase found temperature-sensitive folding steps. Second, computer modeling explored plausible folding sequences starting from the amino acid sequence. Third, computer modeling generated potential folding pathways for cytochrome C, myoglobin, and lysozyme by minimizing energy between segments and allowing manipulation of parts, though uniqueness was not proven. The document suggests protein folding may follow defined sequences of interactions rather than reaching the lowest energy state.

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    Extrait du Journal de Chimie Physique, 1968, 65 no 1, p. 44.

    ARE THERE PATHWAYS FOR PROTEIN FOLDING ?


    by CYRUS LEVINTHAL

    [Massachusetts Institute of Technology, Department of Biology Cambridge, Massachusetts.]

    __________________

    SUMMARY sation more likely. Thus, a pathway of folding means


    that there exist a well-defined sequence of events
    Denatured proteins, which have had essentially all which follow one another so as to carry the protein
    of their native three-dimensional structure disrupted, from the unfolded random coil to a uniquely folded
    can refold from their random disordered state into a metastable state. If the final folded state turned out to
    well-defined unique structure, in which the biological be one of lowest configurational energy, it would be
    activity is virtually completely restored. This experi- a consequence of biological evolution not of physical
    mental result has lead to the suggestion that a native chemistry.
    protein exists in some kind of thermodynamic con- Three approaches have been used in investigating
    figurational equilibrium, with the biologically active this problem. First, the refolding and dimerization of
    state being the one with the lowest configurational the enzyme alkaline phosphatase obtained from the
    energy. An alternative view is that the native protein bacterium E. Coli has been studied under varying
    is in a uniquely selected metastable state, in which conditions and from a variety of mutant strains. Mu-
    the configurational energy is at a local minimum. In tants have been selected which fail to make active
    this latter model, the protein is not assumed to be in enzyme at 44C. About half of these mutants have
    the equilibrium state, and one must postulate some activity when the cells are grown at 25C, and the
    sequence of events which takes place for each mole- enzyme produced at the low temperature has been
    cule so that the protein reaches the correct metastable found to be stable even at low temperatures much
    state. higher than that used in the selection. Thus, these
    One possible sequential process which might lead mutants have a temperature-sensitive step in one of
    a protein to land in a particular state, is the growth of the events which normally leads to the formation of
    the peptide chain on the ribosome, starting with the active enzyme, but the enzyme produced is not tem-
    amino terminal end and proceeding to the carboxy perature sensitive.
    terminus. Although one could imagine a protein A second approach involved the use of computer-
    folding as it grows, and thus attaining a particular aided molecular model building in attempts to deduce
    metastable state, this is clearly not a necessary condi- plausible pathways which proteins can follow as they
    tion for correct folding, at least for those proteins are folding. Starting with an amino acid sequence we
    which have been shown to be reversibly denaturable. can describe the configuration of the protein i.e., the
    However, the fact that folding on the ribosomes is not position of each of its atoms in space if we know the
    necessary for the establishment of structure, does not dihedral angles for the backbone and, in addition, the
    imply that any theory invoking a pathway of folding rotation angle about the appropriate bonds of the
    can be eliminated. Such a pathway only requires amino acid residues. Using a computer controlled
    some local interactions or condensations of segments display system, the molecule thus generated can be
    of the polypeptide chain whenever the denatured displayed in such a way that the observer can see the
    protein is put into the appropriate renaturing medium. three-dimensional relationships in the structure.
    These segments would form unique three- Computer programs have been written in such a way
    dimensional structures which make further conden- that any configuration can be altered to minimize the
    Van der WAALS energy and to insure close packing This system has been used in an attempt to obtain
    of the structure. However, this energy minimization such a pathway of folding for the protein cytochrome
    can only be expected to alter the structure to the bot- C. A plausible structure has been obtained in this way
    tom of the local minimum; it is not intended to search which satisfies all of the known chemical interactions
    through all possible configurations for a true mini- of the molecule. However, the uniqueness of the pro-
    mum energy. In addition, the investigator can alter posed folding process has not been determined.
    the computer generated structure as if he were deal- Finally, the computer system has been used in at-
    ing with physical models in which one part could be tempts to deduce plausible folding pathways for
    pushed or pulled relative to another. Thus, the com- myoglobin and lysozyme. Three-dimensional pictures
    puter-aided model building is not designed to find the of the structures and some of the folding sequences
    configuration of minimum energy rather, it is de- will be shown.
    signed as an aid to the investigator as various se-
    quentially folding steps are tried. Le texte du mmoire ne nous est pas parvenu.

    __________________

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