Peptide nucleic acid Hoogsteen strand linker design for major groove recognition of DNA thymine bases
| Autor: | Christopher M. Topham, Jeremy C. Smith |
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| Rok vydání: | 2020 |
| Předmět: |
Models
Molecular Peptide Nucleic Acids RNA Untranslated Pyrimidine Stereochemistry Stacking Molecular Conformation Alkenes Crystallography X-Ray 01 natural sciences chemistry.chemical_compound 0103 physical sciences Drug Discovery Physical and Theoretical Chemistry Base Pairing Alanine 010304 chemical physics Peptide nucleic acid Uracil Hydrogen Bonding DNA 0104 chemical sciences Computer Science Applications Thymine 010404 medicinal & biomolecular chemistry Cross-Linking Reagents Pyrimidines chemistry Nucleic acid Nucleic Acid Conformation Thermodynamics Peptides Linker |
| Zdroj: | Journal of computer-aided molecular design. 35(3) |
| ISSN: | 1573-4951 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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