TY - JOUR
T1 - Protein folding - seeing is deceiving
AU - Rose, George D.
N1 - Funding Information:
Ι am indebted to Thomas Kiefhaber, Jayanth Banavar, and Tatjana Škrbić for discussion, to Gary Pielak, Peter von Hippel and Loren Williams for discussion and editorial suggestions, to Doug Barrick, Sandhya Bhatia, David Shaw and Jayant Udgaonkar for critical reading of sections that describe their work, and to the National Science Foundation for support.
Publisher Copyright:
© 2021 The Author. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.
PY - 2021/8
Y1 - 2021/8
N2 - This Perspective is intended to raise questions about the conventional interpretation of protein folding. According to the conventional interpretation, developed over many decades, a protein population can visit a vast number of conformations under unfolding conditions, but a single dominant native population emerges under folding conditions. Accordingly, folding comes with a substantial loss of conformational entropy. How is this price paid? The conventional answer is that favorable interactions between and among the side chains can compensate for entropy loss, and moreover, these interactions are responsible for the structural particulars of the native conformation. Challenging this interpretation, the Perspective introduces a proposal that high energy (i.e., unfavorable) excluding interactions winnow the accessible population substantially under physical–chemical conditions that favor folding. Both steric clash and unsatisfied hydrogen bond donors and acceptors are classified as excluding interactions, so called because conformers with such disfavored interactions will be largely excluded from the thermodynamic population. Both excluding interactions and solvent factors that induce compactness are somewhat nonspecific, yet together they promote substantial chain organization. Moreover, proteins are built on a backbone scaffold consisting of α-helices and strands of β-sheet, where the number of hydrogen bond donors and acceptors is exactly balanced. These repetitive secondary structural elements are the only two conformers that can be both completely hydrogen-bond satisfied and extended indefinitely without encountering a steric clash. Consequently, the number of fundamental folds is limited to no more than ~10,000 for a protein domain. Once excluding interactions are taken into account, the issue of “frustration” is largely eliminated and the Levinthal paradox is resolved. Putting the “bottom line” at the top: it is likely that hydrogen-bond satisfaction represents a largely under-appreciated parameter in protein folding models.
AB - This Perspective is intended to raise questions about the conventional interpretation of protein folding. According to the conventional interpretation, developed over many decades, a protein population can visit a vast number of conformations under unfolding conditions, but a single dominant native population emerges under folding conditions. Accordingly, folding comes with a substantial loss of conformational entropy. How is this price paid? The conventional answer is that favorable interactions between and among the side chains can compensate for entropy loss, and moreover, these interactions are responsible for the structural particulars of the native conformation. Challenging this interpretation, the Perspective introduces a proposal that high energy (i.e., unfavorable) excluding interactions winnow the accessible population substantially under physical–chemical conditions that favor folding. Both steric clash and unsatisfied hydrogen bond donors and acceptors are classified as excluding interactions, so called because conformers with such disfavored interactions will be largely excluded from the thermodynamic population. Both excluding interactions and solvent factors that induce compactness are somewhat nonspecific, yet together they promote substantial chain organization. Moreover, proteins are built on a backbone scaffold consisting of α-helices and strands of β-sheet, where the number of hydrogen bond donors and acceptors is exactly balanced. These repetitive secondary structural elements are the only two conformers that can be both completely hydrogen-bond satisfied and extended indefinitely without encountering a steric clash. Consequently, the number of fundamental folds is limited to no more than ~10,000 for a protein domain. Once excluding interactions are taken into account, the issue of “frustration” is largely eliminated and the Levinthal paradox is resolved. Putting the “bottom line” at the top: it is likely that hydrogen-bond satisfaction represents a largely under-appreciated parameter in protein folding models.
KW - Levinthal paradox
KW - backbone-based model
KW - conformational entropy
KW - excluding interactions
KW - hydrogen-bond satisfaction
KW - protein folding
KW - steric clash
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U2 - 10.1002/pro.4096
DO - 10.1002/pro.4096
M3 - Article
C2 - 33938055
AN - SCOPUS:85105618969
SN - 0961-8368
VL - 30
SP - 1606
EP - 1616
JO - Protein Science
JF - Protein Science
IS - 8
ER -