Energetics of oligonucleotide conformational heterogeneity

描述(申请人提供)：DNA和RNA表现出惊人的构象多态，这对于它们广泛的生物学功能是必不可少的，包括复制和基因调节。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，这种多态在寡核苷酸生物学功能中的重要性变得更加明显。寡核苷酸假定的各种构象，无论它们是正则的还是非正则的，都是由它们与环境的相互作用(包括与小分子和蛋白质的相互作用)以及它们的固有构象性质(主要由碱基序列决定)之间的平衡决定的。在这项拟议的研究中，将结合量子力学(QM)和分子动力学(MD)的理论计算，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相加模型，并开发一种新的非相加力场，其中电子的极化率通过经典的Drude振子来显式处理。这些力场，通过MD模拟和平均力势(PMF)计算，将用于确定环境对RNA和DNA性质的贡献，而QM计算将用于确定内在构象性质。将要研究的生物系统包括DNA和RNA的各种规范形式以及非规范形式，包括凸起、发夹和RNA核糖开关。这些系统代表了与序列和环境变化相关的各种寡核苷酸构象，包括与离子的相互作用。通过这些研究，将获得稳定不同构象的力的原子学细节。鉴于从这些研究中获得的见解，与其生物活性相关的DNA或RNA的构象特性将被阐明。这些新发现最终将被用于合理地针对寡核苷酸，如核糖体和核糖开关，以创造例如新的抗生素。此外，在拟议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界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.