Department of Biochemistry and Molecular Biology , Michigan State University , 603 Wilson Road , East Lansing , Michigan 48824 , United States.
J Phys Chem B. 2019 Oct 3;123(39):8168-8177. doi: 10.1021/acs.jpcb.9b05168. Epub 2019 Sep 20.
Peptide nucleic acid (PNA) is a neutral nucleic acid analogue that base pairs with itself and natural nucleic acids. PNA-nucleic acid complexes are more thermally stable than the corresponding complexes of natural nucleic acids. In addition, PNA is biostable and thus used in many antisense and antigene applications to block functional RNA or DNA via sequence-specific interactions. We have recently developed force field parameters for molecular dynamics (MD) simulations of PNA and PNA-involving duplexes with natural nucleic acids. In this work, we provide the first application of this force field to biologically relevant PNA sequences and their complexes with RNA. We investigated thermal stabilities of short PNA-PNA, PNA-RNA, and RNA-RNA duplexes using UV-monitored thermal denaturation experiments and MD simulations at ambient and elevated temperatures. The simulations show a two-state melting transition and reproduce the thermal stability from melting experiments, with PNA-PNA being the most and RNA-RNA the least stable. The PNA-PNA duplex also displays the highest activation energy for melting. The atomistic details of unfolding of PNA duplexes suggest that all PNA-PNA bases melt concomitantly, whereas the RNA-RNA and PNA-RNA are destabilized from the termini toward the central part of the duplexes.
肽核酸（PNA）是一种与自身和天然核酸形成碱基对的中性核酸类似物。PNA-核酸复合物比相应的天然核酸复合物具有更高的热稳定性。此外，PNA 具有生物稳定性，因此在许多反义核酸和基因阻断应用中被用于通过序列特异性相互作用阻断功能性 RNA 或 DNA。我们最近开发了用于 PNA 及其与天然核酸形成的双链体的分子动力学（MD）模拟的力场参数。在这项工作中，我们首次将该力场应用于具有生物学相关性的 PNA 序列及其与 RNA 的复合物。我们使用 UV 监测的热变性实验和环境及升高温度下的 MD 模拟研究了短 PNA-PNA、PNA-RNA 和 RNA-RNA 双链体的热稳定性。模拟显示出两态熔融转变，并再现了熔融实验中的热稳定性，其中 PNA-PNA 最稳定，RNA-RNA 最不稳定。PNA-PNA 双链体的熔融也具有最高的活化能。PNA 双链体解折叠的原子细节表明，所有的 PNA-PNA 碱基都同时熔融，而 RNA-RNA 和 PNA-RNA 则从双链体的末端向中心部分失稳。
