Sugar puckering of nucleosides impacts nucleic acid structures; hence their biological function. Similarly, nucleoside-based therapeutics may adopt different conformations affecting their binding affinity, DNA incorporation, and excision rates. As a result, significant efforts have been made to develop nucleoside analogues adopting specific conformations to improve bioactivity and pharmacokinetic profiles of the corresponding nucleoside-containing drugs. Understanding and ultimately predicting these conformational preferences would significantly help in the design of more effective structures. We report herein a computational study based on hybrid QM/MM umbrella sampling simulations that allow the accurate prediction of the sugar conformational preferences of chemically modified nucleosides in solution. Moreover, we pair these simulations with natural bond orbital (NBO) analysis to gain key insights into the role of substituents in the conformational preferences of these nucleosides.

中文翻译：

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准确建模核苷的构象偏好

核苷的糖皱会影响核酸结构；因此它们的生物学功能。同样，基于核苷的治疗剂可能采用不同的构象，从而影响其结合亲和力，DNA掺入率和切除率。结果，已经做出了巨大的努力来开发采用特定构象的核苷类似物，以改善相应的含核苷药物的生物活性和药代动力学特征。理解并最终预测这些构象偏好将极大地帮助设计更有效的结构。我们在这里报告基于混合QM / MM伞状采样模拟的计算研究，该模拟研究可准确预测溶液中化学修饰核苷的糖构象偏好。而且，