化学合成硒核酸用于核酸晶体生长及机理研究

X- ray crystallography structural biology is essential for determination of the structure and function of nucleic acids. However, the nucleic acid crystal growth is a major obstacle to its structure determination. Because the nucleic acid molecule is very dynamic, flexible and has high-gathered charge, it is difficult for nucleic acid molecule to be high-ordered crystals, thus high-resolution diffraction results can’t be obtained. Our recent study results reveal that Selenium-derivatized DNA and RNA (SeNA) can promote the crystal growth, and high-quality crystal can easily be obtained. We attribute this to the decrease of the dynamic of nucleic acid molecules, the increase of rigidity of nucleic acid molecule and the dispersion of the high-gathered charge, the three of which are caused by selenium atom whose weight is four times larger than the weight of oxygen atom. Therefore, we propose research hypotheses: selenium atom can be introduced to nucleic acid molecule through a high selective replace of oxygen atom. When introduced to nucleic acid molecule, selenium atom can enhance the influences of different regions in nucleic acid molecule on its effective stacking and crystallization. In addition, selenium atom also can strengthen the Van der Waals’ force and the interaction between nucleic acid molecules, contributing to the crystal growth of nucleic acid molecule. It is believed that SeNA can bring a revolutionary promotion in the development of nucleic acid and nucleic acid-protein crystallography structural biology, as well as in the development of nucleic acid conversion biomedicine.

X-光晶体结构生物学对于核酸结构测定和功能研究极其重要。然而，核酸晶体生长是其结构测定的一大障碍。由于核酸分子动态性很强、是柔软的、并且分子带有高聚集的电荷，所以核酸分子很难有序排列堆积成为晶体，并提供高分辨衍射结果。我们的研究结果表明，硒衍生化的DNA和RNA（硒核酸）可以促进核酸晶体生长, 并且可以得到高质量的晶体。我们推断这是由于重量相当于氧原子5倍的硒原子减少了核酸分子的动态性，提高了核酸分子的刚性，并分散了核酸分子的电荷。基础此，我们提出研究假说：通过化学合成进行定点、定位、定原子取代，来引入硒原子替代核酸氧原子，硒原子引入核酸分子后可以被用来加强每一个核苷酸不同的区域对分子有效堆积和结晶的影响。硒的引入还能加强晶体中核酸分子间的范德华力和相互作用，从而可以帮助晶体较快生长。硒核酸将带来核酸及核酸-蛋白结构生物学和核酸转化生物医学的革命性推动。

晶体生长是核酸晶体结构生物学上的一大世界难题。我们在核酸中通过对氧原子的选择性取代来定点定位引入硒原子，硒修饰的核酸即是硒核酸，并且核酸的特异性硒修饰对核酸自身的天然结构几乎没有影响和改变，但其硒核酸功能和特性却大大提高。然而，核酸分子带有负电荷、易酶水解、构象多样性以及制备的核酸分子不均一性，核酸分子很难有序排列堆积成为晶体。然而，我们研究发现硒原子可有效地分散核酸的电荷，增强核酸分子的酶水解，降低其构象多样性，硒原子可提高制备核酸的纯度和均一性，加强分子内和分子间的弱相互作用，提高分子晶体有序堆积的速度和质量。这些研究支持了我们的假说：引入硒原子替代核酸氧原子，从而用硒原子来强化分子有效堆积和结晶。总之，通过核酸的硒原子修饰，我们可望在将来实现有效地和常规地解决核酸及其蛋白复合物晶体生长这一世界难题。