Dipartimento di Chimica, University of Parma, Italy, 43124, Italy.
Department of Chemistry and Applied Biosciences, ETH Zurich, c/o Università della Svizzera Italiana Campus, 6900 Lugano, Switzerland.
Sci Rep. 2017 Feb 17;7:42799. doi: 10.1038/srep42799.
Peptide Nucleic Acids (PNAs) can efficiently target DNA or RNA acting as chemical tools for gene regulation. Their backbone modification and functionalization is often used to increase the affinity for a particular sequence improving selectivity. The understanding of the trading forces that lead the single strand PNA to bind the DNA or RNA sequence is preparatory for any further rational design, but a clear and unique description of this process is still not complete. In this paper we report further insights into this subject, by a computational investigation aiming at the characterization of the conformations of a single strand PNA and how these can be correlated to its capability in binding DNA/RNA. Employing Metadynamics we were able to better define conformational pre-organizations of the single strand PNA and γ-modified PNA otherwise unrevealed through classical molecular dynamics. Our simulations driven on backbone modified PNAs lead to the conclusion that this γ-functionalization affects the single strand preorganization and targeting properties to the DNA/RNA, in agreement with circular dichroism (CD) spectra obtained for this class of compounds. MD simulations on PNA:RNA dissociation and association mechanisms allowed to reveal the critical role of central bases and preorganization in the binding process.
肽核酸 (PNA) 可以有效地靶向 DNA 或 RNA，作为基因调控的化学工具。它们的骨架修饰和功能化经常被用来提高对特定序列的亲和力，从而提高选择性。了解导致单链 PNA 与 DNA 或 RNA 序列结合的相互作用力，是进一步进行任何合理设计的前提，但对这一过程的明确和独特描述仍不完整。在本文中，我们通过计算研究进一步深入探讨了这一主题，旨在描述单链 PNA 的构象及其与结合 DNA/RNA 能力的关系。我们使用元动力学方法，能够更好地定义单链 PNA 的构象预组织，否则通过经典分子动力学方法是无法揭示的。我们对骨架修饰的 PNA 的模拟得出的结论是，这种 γ 功能化会影响单链的预组织和对 DNA/RNA 的靶向特性，这与我们为这类化合物获得的圆二色性 (CD) 光谱一致。对 PNA:RNA 解离和结合机制的 MD 模拟揭示了中心碱基和预组织在结合过程中的关键作用。
