Ge Wei, Schneider Bohdan, Olson Wilma K
Department of Chemistry & Chemical Biology, Rutgers, the State University of New Jersey, Wright-Rieman Laboratories, Piscataway, New Jersey, USA.
Biophys J. 2005 Feb;88(2):1166-90. doi: 10.1529/biophysj.104.043612. Epub 2004 Oct 22.
Elastic ellipsoidal functions defined by the observed hydration patterns around the DNA bases provide a new basis for measuring the recognition of ligands in the grooves of double-helical structures. Here a set of knowledge-based potentials suitable for quantitative description of such behavior is extracted from the observed positions of water molecules and amino acid atoms that form hydrogen bonds with the nitrogenous bases in high resolution crystal structures. Energies based on the displacement of hydrogen-bonding sites on drugs in DNA-crystal complexes relative to the preferred locations of water binding around the heterocyclic bases are low, pointing to the reliability of the potentials and the apparent displacement of water molecules by drug atoms in these structures. The validity of the energy functions has been further examined in a series of sequence substitution studies based on the structures of DNA bound to polyamides that have been designed to recognize the minor-groove edges of Watson-Crick basepairs. The higher energies of binding to incorrect sequences superimposed (without conformational adjustment or displacement of polyamide ligands) on observed high resolution structures confirm the hypothesis that the drug subunits associate with specific DNA bases. The knowledge-based functions also account satisfactorily for the measured free energies of DNA-polyamide association in solution and the observed sites of polyamide binding on nucleosomal DNA. The computations are generally consistent with mechanisms by which minor-groove binding ligands are thought to recognize DNA basepairs. The calculations suggest that the asymmetric distributions of hydrogen-bond-forming atoms on the minor-groove edge of the basepairs may underlie ligand discrimination of G.C from C.G pairs, in addition to the commonly believed role of steric hindrance. The analysis of polyamide-bound nucleosomal structures reveals other discrepancies in the expected chemical design, including unexpected contacts to DNA and modified basepair targets of some ligands. The ellipsoidal potentials thus appear promising as a mathematical tool for the study of drug- and protein-DNA interactions and for gaining new insights into DNA-binding mechanisms.
由DNA碱基周围观察到的水合模式定义的弹性椭球函数为测量双螺旋结构凹槽中配体的识别提供了新的基础。在这里，从高分辨率晶体结构中与含氮碱基形成氢键的水分子和氨基酸原子的观察位置提取了一组适合定量描述这种行为的基于知识的势能。基于DNA-晶体复合物中药物上氢键结合位点相对于杂环碱基周围水结合的优选位置的位移的能量较低，这表明了势能的可靠性以及这些结构中药物原子对水分子的明显取代。基于与聚酰胺结合的DNA结构的一系列序列取代研究进一步检验了能量函数的有效性，这些聚酰胺被设计用于识别沃森-克里克碱基对的小沟边缘。在观察到的高分辨率结构上叠加（不进行聚酰胺配体的构象调整或位移）与不正确序列结合的较高能量证实了药物亚基与特定DNA碱基结合的假设。基于知识的函数也令人满意地解释了溶液中DNA-聚酰胺结合的测量自由能以及聚酰胺在核小体DNA上的结合位点。这些计算通常与小沟结合配体识别DNA碱基对的机制一致。计算表明，除了通常认为的空间位阻作用外，碱基对小沟边缘上形成氢键原子的不对称分布可能是区分G.C和C.G对配体的基础。对聚酰胺结合的核小体结构的分析揭示了预期化学设计中的其他差异，包括与DNA的意外接触以及一些配体的修饰碱基对靶点。因此，椭球势能作为研究药物和蛋白质与DNA相互作用以及深入了解DNA结合机制的数学工具似乎很有前景。
