Energetics of oligonucleotide conformational heterogeneity

描述（由申请人提供）：DNA和RNA表现出惊人程度的构象多态性，这对它们广泛的生物功能至关重要，包括复制和基因调控。随着在真核生物和原核生物中发挥重要作用的非规范结构的发现，这种多态性在寡核苷酸生物学功能中的重要性变得越来越明显。寡核苷酸的各种构象，无论是典型的还是非典型的，都是由它们与环境的相互作用的平衡决定的，包括与小分子和蛋白质的相互作用，以及它们内在的构象性质，很大程度上由碱基序列决定。在拟议的研究中，将使用量子力学（QM）和基于理论计算的分子动力学（MD）的组合在原子水平上详细研究这种平衡。为了实现这一目标，将进一步发展经验力场，重点是改进目前可用的CHARMM27加性模型，并开发一种新的非加性力场，其中电子极化率通过经典德鲁德振荡器明确处理。通过MD模拟和平均力势（PMF）计算，这些力场将用于确定环境对RNA和DNA性质的影响，而QM计算将用于确定内在构象性质。要研究的生物系统包括各种规范形式的DNA和RNA，以及非规范形式，包括凸起，发夹和RNA核糖开关。这些系统代表了各种寡核苷酸构象，这些构象与序列和环境的变化有关，包括与离子的相互作用。从这些研究中，将获得稳定不同构象的力的原子细节。鉴于从这些研究中获得的见解，DNA或RNA与其生物活性相关的构象特性将得到阐明。这些新发现最终将被用于合理地靶向寡核苷酸，例如核糖体和核糖体开关，以创造新的抗生素。此外，在提出的工作中开发的更准确的核酸经验模型将允许理论化学和生物物理学社区对这些系统进行更现实的基于MD的研究。

DESCRIPTION (provided by applicant): DNA and RNA exhibit an amazing degree of conformational polymorphism that is essential for their wide variety of biological functions, including replication and gene regulation. The importance of this polymorphism in the biological functions of oligonucleotides is becoming more evident as discoveries of non-canonical structures that play essential roles in both eukaryotic and prokaryotic organisms are identified. The variety of conformations assumed by oligonucleotides, be they either canonical or non- canonical, are dictated by a balance of interactions with their environment, including interactions with small molecules and proteins, and of their intrinsic conformational properties, largely dictated by the base sequence. In the proposed study this balance will be investigated at an atomic level of detail using a combination of quantum mechanical (QM) and molecular dynamics (MD) based theoretical calculations. Towards this goal, further development of empirical force fields will be undertaken, focusing on improvements in the currently available CHARMM27 additive model and the development of a novel non- additive force field in which electronic polarizability is explicitly treated via classical Drude oscillators. These force fields, via MD simulations and potential of mean force (PMF) calculations, will be used to determine environmental contributions to RNA and DNA properties while QM calculations will be used to determine intrinsic conformational properties. Biological systems to be studied include a variety of canonical forms of DNA and RNA as well as non-canonical forms including bulges, hairpins and a RNA riboswitch. These systems represent a variety of oligonucleotide conformations that are associated with variations in sequence and environment, including interactions with ions. From these investigations atomistic details of the forces stabilizing the different conformations will be obtained. Given the insights gained from these studies, conformational properties of DNA or RNA relevant to their biological activity will be elucidated. These new finding will ultimately be used to rationally target oligonucleotides, such as the ribosome and riboswitches, in order to create, for example, novel antibiotics. Moreover, the more accurate empirical models of nucleic acids developed in the proposed work will allow more realistic MD based studies of these systems by the theoretical chemistry and biophysics communities.