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Halogen bonds as orthogonal molecular interactions to hydrogen bonds

Nature Chemistry volume 1, pages 74–79 (2009)Cite this article

Abstract

Halogen bonds (X-bonds) are shown to be geometrically perpendicular to and energetically independent of hydrogen bonds (H-bonds) that share a common carbonyl oxygen acceptor. This orthogonal relationship is accommodated by the in-plane and out-of-plane electronegative potentials of the oxygen, which are differentially populated by H- and X-bonds. Furthermore, the local conformation of a peptide helps to define the geometry of the H-bond and thus the oxygen surface that is accessible for X-bonding. These electrostatic and steric forces conspire to impose a strong preference for the orthogonal geometry of X- and H-bonds. Thus, the optimum geometry of an X-bond can be predicted from the pattern of H-bonds in a folded protein, enabling X-bonds to be introduced to improve ligand affinities without disrupting these structurally important interactions. This concept of orthogonal molecular interactions can be exploited for the rational design of halogenated ligands as inhibitors and drugs, and in biomolecular engineering.

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Figure 1: H- and X-bond geometries.
Figure 2: Distribution of H- and hX-bonds at the carbonyl oxygen surface in proteins.
Figure 3: Electrostatic potentials and X-bonding interaction energies of the carbonyl oxygen in NEPA (1).
Figure 4: X-bond geometries in β-sheets and α-helices.
Figure 5: Effects of X-bonds and H-bonds on interaction energies of NEPA.

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Acknowledgements

We thank Maximiliano Vallejos and the 2005 Biophysics class at Oregon State University for their help in the ab initio calculations. We also thank P. Andrew Karplus for helpful discussion. This work was funded in part by grants from the National Institutes of Health (RIGM62957) and from the Oregon Medical Research Foundation.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, 1870 Campus Delivery, Colorado State University, Fort Collins, Colorado, 80523-1870, USA

    Andrea Regier Voth & P. Shing Ho

  2. Department of Biochemistry and Biophysics, Oregon State University, Corvallis, 97331-7305, Oregon, USA

    Andrea Regier Voth, Patricia Khuu, Keita Oishi & P. Shing Ho

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  1. Andrea Regier Voth
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  2. Patricia Khuu
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Contributions

A.R.V. and P.K. contributed equally to this work. P.S.H., A.R.V. and P.K. analysed and interpreted results, and contributed to writing the manuscript. K.O. performed calculations for this study.

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Correspondence to P. Shing Ho.

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Voth, A., Khuu, P., Oishi, K. et al. Halogen bonds as orthogonal molecular interactions to hydrogen bonds. Nature Chem 1, 74–79 (2009). https://doi.org/10.1038/nchem.112

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