Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
Nucleosides Nucleotides Nucleic Acids. 2024;43(9):935-950. doi: 10.1080/15257770.2024.2302526. Epub 2024 Jan 11.
Recently, we found DNA/RNA heteroduplex oligonucleotide-based antimiR (HDO-antimiR) can more efficiently inhibit the target miRNA than conventional antimiR after its cellular uptake. But the mechanism of HDO-antimiR about the target-silencing is unknown. We here tried to elucidate the interaction mechanism of HDO-antimiR to miRNA using molecular dynamics (MD) simulation. When interaction of the conventional antimiR or HDO-antimiR and the target miRNA was simulated, they combined with each other in various forms. In the hydrogen bond analyses, base site of the antimiR formed hydrogen bond with miRNA. On the other hand, phosphate site of the HDO-antimiR formed hydrogen bond with miRNA. These results suggested that there were differences about the binding mechanisms between antimiR and HDO-antimiR to the target miRNA. In particular, there was a difference in the binding site between antimiR and HDO-antimiR. Additionally, it was found that guanine in the miRNA is mainly involved in the binding to the antimiR or HDO-antimiR. MD simulation method is useful in understanding the mechanism of oligonucleotide therapeutics.
最近，我们发现 DNA/RNA 杂合寡核苷酸基抗 miRNA（HDO-antimiR）在细胞摄取后比传统的 antimiR 更能有效地抑制靶 miRNA。但 HDO-antimiR 关于靶沉默的机制尚不清楚。我们在这里尝试使用分子动力学（MD）模拟来阐明 HDO-antimiR 与 miRNA 的相互作用机制。当模拟传统的 antimiR 或 HDO-antimiR 与靶 miRNA 的相互作用时，它们以各种形式结合在一起。在氢键分析中，antimiR 的碱基与 miRNA 形成氢键。另一方面，HDO-antimiR 的磷酸基团与 miRNA 形成氢键。这些结果表明，antimiR 和 HDO-antimiR 与靶 miRNA 的结合机制存在差异。特别是，antimiR 和 HDO-antimiR 的结合位点存在差异。此外，还发现 miRNA 中的鸟嘌呤主要参与与 antimiR 或 HDO-antimiR 的结合。MD 模拟方法有助于理解寡核苷酸治疗的机制。
