Impact of bPNA Backbone Structural Constraints and Composition on Triplex Hybridization with DNA.
Impact of bPNA Backbone Structural Constraints and Composition on Triplex Hybridization with DNA.
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DOI：
10.1002/cbic.202100707
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发表时间：
2022-04-20
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我们在此报告的双面肽核酸（bPNA）的氨基酸组成和骨架修饰对DNA结合的影响的研究。合成一系列具有相同净电荷的bPNA骨架变体以展示4或6个三聚氰胺（M）碱基。这些碱基形成胸腺嘧啶-三聚氰胺-胸腺嘧啶（TMT）碱基三联体，导致具有富含T的DNA的三链体杂交茎结构。6 M bPNA-DNA杂交的分析表明，杂交稳定性与氨基酸二级结构倾向有关，这促使在较短的4 M bPNAs中进行更详细的研究。我们合成了4 M bPNAs倾向于采用螺旋二级结构通过螺旋转弯成核7残基bPNAs使用双击共价钉合。通常，杂交稳定性在钉合后改善，但氨基酸组成具有更显著的影响。我们还寻求一种替代策略bPNA结构预组织的残基与强大的骨干酰胺构象偏好，如4 R和4S-氟脯氨酸的掺入。值得注意的是，这些衍生物在杂交稳定性方面表现出超过未取代的脯氨酸bPNA类似物和螺旋图案化的bPNA的额外改善。总之，这些发现证明了bPNA-DNA杂交稳定性通过bPNA骨架结构倾向和氨基酸组成的可调性。bPNAs的主链限制和氨基酸组成对与DNA的三链体杂交产生微妙的影响。限制骨架构象的设计元素有利于杂交，但保守氨基酸突变也会对杂交稳定性产生显著影响。
We report herein a study on the impact of bifacial peptide nucleic acid (bPNA) amino acid composition and backbone modification on DNA binding. A series of bPNA backbone variants with identical net charge were synthesized to display either 4 or 6 melamine (M) bases. These bases form thymine-melamine-thymine (TMT) base-triples, resulting in triplex hybrid stem structures with T-rich DNAs. Analyses of 6M bPNA-DNA hybrids suggested that hybrid stability was linked to amino acid secondary structure propensities, prompting a more detailed study in shorter 4M bPNAs. We synthesized 4M bPNAs predisposed to adopt helical secondary structure via helix-turn nucleation in 7-residue bPNAs using double-click covalent stapling. Generally, hybrid stability improved upon stapling, but amino acid composition had a more significant effect. We also pursued an alternative strategy for bPNA structural preorganization by incorporation of residues with strong backbone amide conformational preferences such as 4R and 4S-fluoroprolines. Notably, these derivatives exhibited an additional improvement in hybrid stability beyond both unsubstituted proline bPNA analogs and the helically patterned bPNAs. Overall, these findings demonstrate the tunability of bPNA-DNA hybrid stability through bPNA backbone structural propensities and amino acid composition. Backbone constraints and amino acid composition of bPNAs exert subtle effects on triplex hybridization with DNA. Design elements that limit backbone conformation favor hybridization, but conservative amino acid mutations can also have a significant effect on hybrid stability.
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