Hayatshahi Hamed S, Henriksen Niel M, Cheatham Thomas E
Department of Medicinal Chemistry, College of Pharmacy, L. S. Skaggs Pharmacy Research Institute , University of Utah , Salt Lake City , Utah 84112-5820 , United States.
Skaggs School of Pharmacy and Pharmaceutical Sciences , University of California at San Diego , 9500 Gilman Drive , MC 0736, La Jolla , California 92093 , United States.
J Chem Theory Comput. 2018 Mar 13;14(3):1456-1470. doi: 10.1021/acs.jctc.7b00581. Epub 2018 Feb 6.
Dinucleoside monophosphates (DNMPs) have been described using various experimental approaches as flexible molecules which generate ensembles populating at least a small set of different conformations in solution. However, due to limitations of each approach in its ability to delineate the ensemble of conformations, an accurate and quantitative description of certain conformational features has not been performed for all DNMPs. Here, we apply a temperature replica-exchange molecular dynamics approach to fully and quickly converge conformational distributions of all RNA DNMPs immersed in the TIP3P water model using the AMBER ff14 force field. For a selection of DNMPs, the conformational ensembles were also generated when immersed in the OPC water model using alternative AMBER and CHARMM force fields. The OPC water model and other force field choices did not introduce new conformational classes but shifted the populations among existing conformations. Except for pyrimidine-pyrimidine dinucleosides, all other DNMPs populated four major conformations (which are defined in the main text and labeled A-form, Ladder, Inverted, and Sheared), in addition to an Extended form. Pyrimidine-pyrimidines did not generate the Sheared conformation. Distinguishing features and stabilizing factors of each conformation were identified and assessed based on the known experimental interpretations. The configuration of the glycosidic bond and the nonbonding interactions of hydrogen bond acceptors with the 2'-hydroxyl group were found to play determining roles in stabilizing particular conformations which could serve as a guide for potential force field modifications to improve the accuracy. Additionally, we computed stacking free energies based on the DNMP conformational distributions and found significant discrepancies with a previous study. Our investigation determined that the AMBER force field was incorrectly implemented in the previous study. In the future, this simulation approach can be used to quickly analyze the effects of new force field modifications in shifting the conformational populations of DNMPs, and can can be further applied to foresee such effects in larger RNA motifs including tetranucleotides and tetraloops.
二核苷单磷酸（DNMPs）已通过各种实验方法被描述为灵活的分子，这些分子在溶液中会形成至少包含一小部分不同构象的集合。然而，由于每种方法在描绘构象集合能力上的局限性，并非所有DNMPs都对某些构象特征进行了准确和定量的描述。在此，我们应用温度复制交换分子动力学方法，使用AMBER ff14力场，全面且快速地收敛浸没在TIP3P水模型中的所有RNA DNMPs的构象分布。对于选定的DNMPs，当浸没在OPC水模型中并使用替代的AMBER和CHARMM力场时，也生成了构象集合。OPC水模型和其他力场选择并未引入新的构象类别，而是改变了现有构象之间的分布。除了嘧啶 - 嘧啶二核苷外，所有其他DNMPs除了一种伸展形式外，还具有四种主要构象（在正文中定义并标记为A形式、梯子形、反向形和剪切形）。嘧啶 - 嘧啶二核苷不会产生剪切形构象。基于已知的实验解释，确定并评估了每种构象的区别特征和稳定因素。发现糖苷键的构型以及氢键受体与2'-羟基的非键相互作用在稳定特定构象中起决定性作用，这可为潜在的力场修改提供指导以提高准确性。此外，我们基于DNMP构象分布计算了堆积自由能，发现与先前的一项研究存在显著差异。我们的研究确定先前的研究中AMBER力场的实施有误。未来，这种模拟方法可用于快速分析新的力场修改对DNMPs构象分布变化的影响，并且可进一步应用于预测在更大的RNA基序（包括四核苷酸和四环）中的此类影响。
