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Local and macroscopic electrostatic interactions in single α-helices

Nature Chemical Biology volume 11, pages 221228 (2015) | Download Citation

  • A Corrigendum to this article was published on 18 August 2015

This article has been updated

Abstract

The noncovalent forces that stabilize protein structures are not fully understood. One way to address this is to study equilibria between unfolded states and α-helices in peptides. Electrostatic forces—which include interactions between side chains, the backbone and side chains, and side chains and the helix macrodipole—are believed to contribute to these equilibria. Here we probe these interactions experimentally using designed peptides. We find that both terminal backbone–side chain and certain side chain–side chain interactions (which include both local effects between proximal charges and interatomic contacts) contribute much more to helix stability than side chain–helix macrodipole electrostatics, which are believed to operate at larger distances. This has implications for current descriptions of helix stability, the understanding of protein folding and the refinement of force fields for biomolecular modeling and simulations. In addition, this study sheds light on the stability of rod-like structures formed by single α-helices, which are common in natural proteins such as non-muscle myosins.

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Change history

  • 05 June 2015

    In the version of this article initially published, two pairs of citations of Figures 4b and 4c were inadvertently switched. The errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

D.N.W. would like to dedicate this paper to the memory of Prof. Dudley H. William FRS, an inspirational scientist, mentor and person. We are grateful to the Engineering and Physical Sciences Research Council (EPSRC) of the UK for a studentship to E.G.B. and the EPSRC/National Science Foundation (EP/J001430) for a grant to D.N.W. that funded G.J.B. D.N.W. holds a Royal Society Wolfson Research Merit Award. We thank C. Wood for a script to align helical axes; M. Peckham and A. Mulholland, and members of the Woolfson and Faul groups, for helpful discussions; and S. Whittaker and the Henry Wellcome Building NMR facility at the University of Birmingham for access to the Wellcome Trust–funded 900 MHz spectrometer.

Author information

Affiliations

  1. School of Chemistry, University of Bristol, Bristol, UK.

    • Emily G Baker
    • , Gail J Bartlett
    • , Matthew P Crump
    • , Charl F J Faul
    •  & Derek N Woolfson
  2. School of Biochemistry, University of Bristol, Bristol, UK.

    • Richard B Sessions
    •  & Derek N Woolfson
  3. School of Mathematics, University of Bristol, Bristol, UK.

    • Noah Linden

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Contributions

E.G.B., C.F.J.F. and D.N.W. designed the research; E.G.B. made the synthetic peptides and performed the CD spectroscopy; M.P.C. and E.G.B. collected and analyzed the NMR data; G.J.B., E.G.B. and D.N.W. performed the bioinformatics; E.G.B. and R.B.S. constructed and analyzed atomistic models for the peptides; N.L. performed and analyzed the helix-dipole calculations; E.G.B., G.J.B. and D.N.W. wrote the paper. All authors reviewed and contributed to the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Derek N Woolfson.

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    Supplementary Text and Figures

    Supplementary Results, Supplementary Figures 1–43 and Supplementary Tables 1–9.

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DOI

https://doi.org/10.1038/nchembio.1739

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