微小RNA(miRNA)是许多疾病的有吸引力的候选药物,因为它们可以调节基因网络的表达。最近,我们发现靶向microRNA-22-3p(miR-22-3p)的DNA具有治疗肥胖和相关代谢紊乱(2型糖尿病,高脂血症,和非酒精性脂肪性肝病(NAFLD))通过将脂肪储存的白色脂肪细胞转化为燃烧脂肪的脂肪细胞。在这项工作中,我们探索了化学修饰的影响,包括硫代磷酸酯(PS),锁定核酸(LNA),和肽核酸(PNA),通过使用分子动力学(MD)模拟来研究DNA类似物的结构和能量。为了实现杂交自由能的可靠预测,采用了AMOEBA极化力场和自由能摄动技术。计算的杂化自由能通常与先前的实验相容。对于LNA和PNA,增强的双工稳定性可以用预组织机制来解释,即,单链采用与双链体相似的稳定螺旋结构。对于PS,S和R异构体(Sp和Rp)对C2\'-endo和C3\'-endo糖起皱构象具有偏好,分别,因此,在DNA/RNA杂交体中,Sp比Rp更不稳定。此外,Rp的溶剂化惩罚解释了其不稳定效应。PS-LNA类似于LNA,因为糖起皱由锁定的糖环主导。这项工作表明,具有可极化力场的MD模拟对于理解和设计修饰的核酸很有用。
MicroRNAs (miRNAs) are attractive drug candidates for many diseases as they can modulate the expression of gene networks. Recently, we discovered that DNAs targeting microRNA-22-3p (miR-22-3p) hold the potential for treating obesity and related metabolic disorders (type 2 diabetes mellitus, hyperlipidemia, and nonalcoholic fatty liver disease (NAFLD)) by turning fat-storing white adipocytes into fat-burning adipocytes. In this work, we explored the effects of chemical modifications, including phosphorothioate (PS), locked nucleic acid (LNA), and peptide nucleic acid (PNA), on the structure and energy of DNA analogs by using molecular dynamics (MD) simulations. To achieve a reliable prediction of the hybridization free energy, the AMOEBA polarizable force field and the free energy perturbation technique were employed. The calculated hybridization free energies are generally compatible with previous experiments. For LNA and PNA, the enhanced duplex stability can be explained by the preorganization mechanism, i.e., the single strands adopt stable helical structures similar to those in the duplex. For PS, the S and R isomers (Sp and Rp) have preferences for C2\'-endo and C3\'-endo sugar puckering conformations, respectively, and therefore Sp is less stable than Rp in DNA/RNA hybrids. In addition, the solvation penalty of Rp accounts for its destabilization effect. PS-LNA is similar to LNA as the sugar puckering is dominated by the locked sugar ring. This work demonstrated that MD simulations with polarizable force fields are useful for the understanding and design of modified nucleic acids.