Interdisciplinary Centre for Mathematical and Computational Modelling, University of Warsaw, Warsaw, Poland.
J Mol Model. 2012 Jun;18(6):2727-40. doi: 10.1007/s00894-011-1272-4. Epub 2011 Nov 25.
Lincosamides are a class of antibiotics used both in clinical and veterinary practice for a wide range of pathogens. This group of drugs inhibits the activity of the bacterial ribosome by binding to the 23S RNA of the large ribosomal subunit and blocking protein synthesis. Currently, three X-ray structures of the ribosome in complex with clindamycin are available in the Protein Data Bank, which reveal that there are two distinct conformations of the pyrrolidinyl propyl group of the bound clindamycin. In this work, we used quantum mechanical methods to investigate the probable conformations of clindamycin in order to explain the two binding modes in the ribosomal 23S RNA. We studied three lincosamide antibiotics: clindamycin, lincomycin, and pirlimycin at the B3LYP level with the 6-31G** basis set. The focus of our work was to connect the conformational landscape and electron densities of the two clindamycin conformers found experimentally with their physicochemical properties. For both functional conformers, we applied natural bond orbital (NBO) analysis and the atoms in molecules (AIM) theory, and calculated the NMR parameters. Based on the results obtained, we were able to show that the structure with the intramolecular hydrogen bond C=O…H-O is the most stable conformer of clindamycin. The charge transfer between the pyrrolidine-derivative ring and the six-atom sugar (methylthiolincosamide), which are linked via an amide bond, was found to be the dominant factor influencing the high stability of this conformer.
林可酰胺类抗生素在临床和兽医实践中被广泛用于治疗多种病原体。该类药物通过与核糖体大亚基的 23S RNA 结合，抑制核糖体的活性，从而阻断蛋白质合成。目前，在蛋白质数据库中已有三种克林霉素与核糖体复合物的 X 射线结构，这些结构揭示了结合的克林霉素的吡咯烷基丙基部分有两种不同的构象。在这项工作中，我们使用量子力学方法研究克林霉素的可能构象，以解释核糖体 23S RNA 中的两种结合模式。我们研究了三种林可酰胺类抗生素：克林霉素、林可霉素和吡利霉素，在 B3LYP 水平上使用 6-31G**基组。我们工作的重点是将实验中发现的两种克林霉素构象的构象景观和电子密度与其物理化学性质联系起来。对于这两种功能构象，我们应用了自然键轨道（NBO）分析和分子中的原子（AIM）理论，并计算了 NMR 参数。基于所得结果，我们能够表明具有分子内 C=O…H-O 氢键的结构是克林霉素最稳定的构象。吡咯烷衍生物环与通过酰胺键连接的六原子糖（甲基硫代林可酰胺）之间的电荷转移被发现是影响这种构象高稳定性的主要因素。
