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Peptide nucleic acid Hoogsteen strand linker design for major groove recognition of DNA thymine bases

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Abstract

Sequence-specific targeting of double-stranded DNA and non-coding RNA via triple-helix-forming peptide nucleic acids (PNAs) has attracted considerable attention in therapeutic, diagnostic and nanotechnological fields. An E-base (3-oxo-2,3-dihydropyridazine), attached to the polyamide backbone of a PNA Hoogsteen strand by a side-chain linker molecule, is typically used in the hydrogen bond recognition of the 4-oxo group of thymine and uracil nucleic acid bases in the major groove. We report on the application of quantum chemical computational methods, in conjunction with spatial constraints derived from the experimental structure of a homopyrimidine PNA·DNA-PNA hetero-triplex, to investigate the influence of linker flexibility on binding interactions of the E-base with thymine and uracil bases in geometry-optimised model systems. Hydrogen bond formation between the N2 E-base atom and target pyrimidine base 4-oxo groups in model systems containing a β-alanine linker (J Am Chem Soc 119:11116, 1997) was found to incur significant internal strain energy and the potential disruption of intra-stand aromatic base stacking interactions in an oligomeric context. In geometry-optimised model systems containing a 3-trans olefin linker (Bioorg Med Chem Lett 14:1551, 2004) the E-base swung out away from the target pyrimidine bases into the solvent. These findings are in qualitative agreement with calorimetric measurements in hybridisation experiments at T–A and U–A inversion sites. In contrast, calculations on a novel 2-cis olefin linker design indicate that it could permit simultaneous E-base hydrogen bonding with the thymine 4-oxo group, circumvention and solvent screening of the thymine 5-methyl group, and maintenance of triplex intra-stand base stacking interactions.

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Acknowledgements

We thank Dr. Richard Lavery for making the CURVES and JUMNA computer programs available to us. CMT is grateful to the University of Tennessee and the Oak Ridge Institute for Science and Education (ORISE) for the award of visiting scholarships.

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Authors and Affiliations

  1. Molecular Forces Consulting, 24 Avenue Jacques Besse, 81500, Lavaur, France

    Christopher M. Topham

  2. Computational Molecular Biophysics, IWR Der Universität Heidelberg, Im Neuenheimer Feld 368, 69120, Heidelberg, Germany

    Christopher M. Topham & Jeremy C. Smith

  3. Center for Molecular Biophysics, University of Tennessee / Oak Ridge National Laboratory, P.O.Box 2008, Oak Ridge, TN, 37831-6309, USA

    Christopher M. Topham & Jeremy C. Smith

  4. Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, M407 Walters Life Sciences, 1414 Cumberland Avenue, Knoxville, TN, 37996, USA

    Christopher M. Topham & Jeremy C. Smith

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  1. Christopher M. Topham
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Correspondence to Christopher M. Topham.

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Topham, C.M., Smith, J.C. Peptide nucleic acid Hoogsteen strand linker design for major groove recognition of DNA thymine bases. J Comput Aided Mol Des 35, 355–369 (2021). https://doi.org/10.1007/s10822-021-00375-9

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