Department of Applied Physics, Aalto University, P.O. Box 11100, FI-00076 Aalto, Finland.
J Phys Chem B. 2012 Sep 6;116(35):10676-83. doi: 10.1021/jp3046577. Epub 2012 Aug 28.
Experiments have shown that two water-soluble fullerene C(60) derivatives, fullerenol and fullerene trimalonic acid, inhibit duplication of DNA via polymerase chain reaction (PCR). It has further been shown that the target of this inhibition is the DNA polymerase protein routinely used in PCR. We have used a combination of molecular docking and molecular dynamics simulations to study the possible DNA polymerase inhibition mechanisms in atomistic detail. The simulations show structural changes in the tip and two alpha helices of a subdomain, crucial for the polymerase activity, upon fullerene derivative binding. Such tertiary structure changes could prevent the binding of DNA to the protein, causing the inhibition of the PCR process. These findings are in agreement with experimental studies, which have shown that the inhibition is not competitive. The proposed mechanism of inhibition would be common for all DNA polymerase proteins, providing new possibilities in antiviral applications of fullerene derivatives.
实验表明，两种水溶性富勒烯 C(60)衍生物——富勒醇和富勒烯丙二酸——可以通过聚合酶链反应（PCR）抑制 DNA 的复制。进一步的研究表明，这种抑制作用的靶标是 PCR 中常用的 DNA 聚合酶蛋白。我们结合分子对接和分子动力学模拟，从原子尺度详细研究了可能的 DNA 聚合酶抑制机制。模拟结果显示，在富勒烯衍生物结合后，亚结构域的尖端和两个α螺旋发生了结构变化，这对聚合酶的活性至关重要。这种三级结构的变化可能会阻止 DNA 与蛋白质的结合，从而抑制 PCR 过程。这些发现与实验研究一致，实验表明这种抑制作用是非竞争性的。所提出的抑制机制可能对所有 DNA 聚合酶蛋白都适用，为富勒烯衍生物在抗病毒方面的应用提供了新的可能性。
