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nπ* interactions in proteins

Abstract

Hydrogen bonds between backbone amides are common in folded proteins. Here, we show that an intimate interaction between backbone amides also arises from the delocalization of a lone pair of electrons (n) from an oxygen atom to the antibonding orbital (π*) of the subsequent carbonyl group. Natural bond orbital analysis predicted significant nπ* interactions in certain regions of the Ramachandran plot. These predictions were validated by a statistical analysis of a large, non-redundant subset of protein structures determined to high resolution. The correlation between these two independent studies is striking. Moreover, the nπ* interactions are abundant and especially prevalent in common secondary structures such as α-, 310- and polyproline II helices and twisted β-sheets. In addition to their evident effects on protein structure and stability, nπ* interactions could have important roles in protein folding and function, and merit inclusion in computational force fields.

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Figure 1: Kinship of hydrogen bonds and nπ* interactions in an α-helix.
Figure 2: Ramachandran plots of nπ* interactions.
Figure 3: Histograms of d and θ values for Xaa-Ala, Xaa-Gly and Xaa-Pro dipeptides in α-helices, β-sheets and PII helices.
Figure 4: Values of d and θ in nπ* interactions.
Figure 5: Potential nπ* interactions in the selectivity filter of the KcsA K+ channel.

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Acknowledgements

We thank J. Spencer, J. Harvey, A. Mulholland, B. Bromley, M.D. Shoulders, B.R. Caes, C.N. Bradford, M.J. Palte and E. Moutevelis for helpful discussions. Financial support was provided by the University of Bristol and the Biotechnology and Biological Sciences Research Council of the United Kingdom (grant D003016) to D.N.W. and the US National Institutes of Health grant R01 AR044276 to R.T.R.

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D.N.W. and R.T.R. conceived the project. G.J.B. and D.N.W. designed the PDB analyses; G.J.B. performed the PDB analyses. A.C. and R.T.R. designed the computational analyses; A.C. performed the computational analyses. All of the coauthors wrote and edited the manuscript.

Corresponding authors

Correspondence to Ronald T Raines or Derek N Woolfson.

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The authors declare no competing financial interests.

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Bartlett, G., Choudhary, A., Raines, R. et al. nπ* interactions in proteins. Nat Chem Biol 6, 615–620 (2010). https://doi.org/10.1038/nchembio.406

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