Lomakin A, Frank-Kamenetskii M D
Physics Department Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
J Mol Biol. 1998 Feb 13;276(1):57-70. doi: 10.1006/jmbi.1997.1497.
We treat theoretically the problem of the specificity of interaction between nucleic acid and an oligonucleotide, its analog or its mimic (such as peptide nucleic acid, or PNA). We consider simplest models with only essential details using numerical solutions of kinetic equations and the kinetic Monte Carlo method. In our first model, describing the formation of complementary duplex, we demonstrate anti-correlation between specificity and affinity for nucleic acid/oligonucleotide interaction. We analyze in detail one notable exception. Homopyrimidine PNAs exhibit very high affinity to DNA forming extraordinarily stable DNA/(PNA)2 triplexes with the complementary DNA strand. At the same time, such PNAs show remarkable sequence specificity of binding to duplex DNA. We formulate a theoretical model for the two-step process of PNA interaction with DNA. The calculations demonstrate that two-stage binding may secure both high affinity and very high specificity of PNA interaction with DNA. Our computer simulations define the range of parameter values in which high specificity is achieved. These findings are of great importance for numerous applications of PNA and for design of future drugs which specifically interact with DNA.
我们从理论上探讨了核酸与寡核苷酸、其类似物或模拟物（如肽核酸，即PNA）之间相互作用的特异性问题。我们使用动力学方程的数值解和动力学蒙特卡罗方法，考虑了仅包含基本细节的最简单模型。在我们的第一个描述互补双链形成的模型中，我们证明了核酸/寡核苷酸相互作用的特异性和亲和力之间存在反相关关系。我们详细分析了一个显著的例外情况。同型嘧啶PNA对DNA表现出非常高的亲和力，能与互补DNA链形成极其稳定的DNA/(PNA)2三链体。同时，这类PNA在与双链DNA结合时显示出显著的序列特异性。我们为PNA与DNA相互作用的两步过程建立了一个理论模型。计算结果表明，两步结合可以确保PNA与DNA相互作用既有高亲和力又有非常高的特异性。我们的计算机模拟确定了实现高特异性的参数值范围。这些发现对于PNA的众多应用以及未来与DNA特异性相互作用的药物设计具有重要意义。
