Abstract
Protein science is being transformed by powerful computational methods for structure prediction and design: AlphaFold2 can predict many natural protein structures from sequence, and other AI methods are enabling the de novo design of new structures. This raises a question: how much do we understand the underlying sequence-to-structure/function relationships being captured by these methods? This perspective presents our current understanding of one class of protein assembly, the α-helical coiled coils. At first sight, these are straightforward: sequence repeats of hydrophobic (h) and polar (p) residues, (hpphppp)n, direct the folding and assembly of amphipathic α helices into bundles. However, many different bundles are possible: they can have two or more helices (different oligomers); the helices can have parallel, antiparallel or mixed arrangements (different topologies); and the helical sequences can be the same (homomers) or different (heteromers). Thus, sequence-to-structure relationships must be present within the hpphppp repeats to distinguish these states. I discuss the current understanding of this problem at three levels: First, physics gives a parametric framework to generate the many possible coiled-coil backbone structures. Second, chemistry provides a means to explore and deliver sequence-to-structure relationships. Third, biology shows how coiled coils are adapted and functionalized in nature, inspiring applications of coiled coils in synthetic biology. I argue that the chemistry is largely understood; the physics is partly solved, though the considerable challenge of predicting even relative stabilities of different coiled-coil states remains; but there is much more to explore in the biology and synthetic biology of coiled coils.
Original language | English |
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Article number | 104579 |
Journal | Journal of Biological Chemistry |
Volume | 299 |
Issue number | 4 |
DOIs | |
Publication status | Published - 3 Mar 2023 |
Bibliographical note
Funding Information:D. N. W. is supported by grants from the Biotechnology and Biological Sciences Research Council (BBSRC): BB/S002820/1; BB/V004220/1; and BB/V006231/1. D. N. W. is also grateful to the University of Bristol for supporting the Max Planck-Bristol Centre for Minimal Biology, the BBSRC for funding the BrisSynBio (BB/L01386X/1) and BrisEngBio (BB/W013959/1) research centers, and the Royal Society for a Wolfson Research Merit Award (WM140008).
Publisher Copyright:
© 2023 The Author
Research Groups and Themes
- Bristol BioDesign Institute
- BrisSynBio
- BrisEngBio
- Max Planck Bristol