Research Center for Analytical Sciences, College of Chemistry, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Nankai University, Tianjin 300071, China.
UMR 7019, Theoretical Physics and Chemistry Department (LPCT), Université de Lorraine-Nancy, 54506 Vandoeuvre-lès-Nancy, France.
Molecules. 2018 Jan 25;23(2):228. doi: 10.3390/molecules23020228.
DNA is the target of chemical compounds (drugs, pollutants, photosensitizers, etc.), which bind through non-covalent interactions. Depending on their structure and their chemical properties, DNA binders can associate to the minor or to the major groove of double-stranded DNA. They can also intercalate between two adjacent base pairs, or even replace one or two base pairs within the DNA double helix. The subsequent biological effects are strongly dependent on the architecture of the binding motif. Discriminating between the different binding patterns is of paramount importance to predict and rationalize the effect of a given compound on DNA. The structural characterization of DNA complexes remains, however, cumbersome at the experimental level. In this contribution, we employed all-atom molecular dynamics simulations to determine the standard binding free energy of DNA with netropsin, a well-characterized antiviral and antimicrobial drug, which associates to the minor groove of double-stranded DNA. To overcome the sampling limitations of classical molecular dynamics simulations, which cannot capture the large change in configurational entropy that accompanies binding, we resort to a series of potentials of mean force calculations involving a set of geometrical restraints acting on collective variables.
DNA 是化学化合物（药物、污染物、光增敏剂等）的靶标，这些化合物通过非共价相互作用结合。根据其结构和化学性质，DNA 结合物可以与双链 DNA 的小沟或大沟结合。它们也可以在两个相邻碱基对之间插入，甚至可以在 DNA 双螺旋中取代一个或两个碱基对。随后的生物学效应强烈依赖于结合基序的结构。区分不同的结合模式对于预测和合理化给定化合物对 DNA 的影响至关重要。然而，在实验水平上，DNA 配合物的结构表征仍然很繁琐。在本研究中，我们采用全原子分子动力学模拟来确定与 netropsin 的标准结合自由能，netropsin 是一种具有良好特征的抗病毒和抗菌药物，与双链 DNA 的小沟结合。为了克服经典分子动力学模拟在采样方面的限制，这些限制无法捕捉到伴随结合而来的构象熵的巨大变化，我们求助于一系列平均力势计算，其中涉及一组作用于集体变量的几何约束。
