Energetics of oligonucleotide conformational heterogeneity

寡核苷酸构象异质性的能量学

• 批准号: 7936632
• 负责人: ALEXANDER D MACKERELL
• 金额: $ 4.7万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7936632
• 关键词: Amaze; Antibiotics; Base Sequence; Biological; Biological Process; Biophysics; Carbohydrates; Chemistry; Communities; Complex; DNA; Data; Development; Electronics; Environment; Equilibrium; Exhibits; Gene Expression Regulation; Genetic Polymorphism; Goals; Heterogeneity; Investigation; Ions; Lipids; Mechanics; Methods; Modeling; Molecular Conformation; Nucleic Acids; Nucleosides; Nucleotides; Oligonucleotides; Organism; Participant; Play; Property; Proteins; RNA; Ribosomes; Role; Structure; Structure-Activity Relationship; System; Testing; Theoretical Studies; Variant; Vertebral column; Work; base; biological systems; field study; improved; insight; interest; model development; molecular dynamics; novel; nucleic acid structure; phosphodiester; quantum; small molecule; success; sugar; tool

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.

描述（由申请人提供）：DNA和RNA表现出惊人的构象多态性，这对于它们的各种生物学功能（包括复制和基因调节）至关重要。这种多态性在寡核苷酸的生物学功能中的重要性变得越来越明显，因为发现在真核和原核生物体中扮演着重要作用的非典型结构的发现。寡核苷酸假设的各种构象，无论是规范还是非规范，都取决于与环境的相互作用平衡，包括与小分子和蛋白质的相互作用及其内在构象性能，其本质上很大程度上由基本序列决定。在拟议的研究中，将使用基于量子力学（QM）和分子动力学（MD）理论计算的组合在原子能水平上研究这种平衡。为了实现这一目标，将进一步发展经验力场，重点是改进当前可用的CHARMM27添加剂模型，并开发新的非添加剂场，其中通过经典的Drude振荡器明确处理了电子极化性。这些力场通过MD模拟和平均力（PMF）计算的潜力来确定对RNA和DNA特性的环境贡献，而QM计算将用于确定固有构象性能。要研究的生物系统包括多种规范形式的DNA和RNA以及非典型形式，包括凸起，发夹和RNA核糖开关。这些系统代表了各种与序列和环境变化相关的寡核苷酸构象，包括与离子的相互作用。从这些研究中，将获得稳定力的原子细节。鉴于从这些研究中获得的见解，将阐明与其生物学活性相关的DNA或RNA的构象性能。这些新发现最终将用于理性地靶向寡核苷酸，例如核糖体和核糖开关，以创建例如新型抗生素。此外，在拟议的工作中开发的核酸的更准确的经验模型将允许通过理论化学和生物物理学对这些系统进行更现实的基于MD的研究。