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表现出惊人程度的构象多态性，这对于其广泛的生物学功能（包括复制和基因调节）至关重要。随着在真核生物和原核生物中起重要作用的非典型结构的发现，这种多态性在寡核苷酸生物功能中的重要性变得越来越明显。寡核苷酸所呈现的构象的多样性，无论是典型的还是非典型的，都由与其环境的相互作用（包括与小分子和蛋白质的相互作用）的平衡以及其内在构象性质（主要由碱基序列决定）的平衡决定。在拟议的研究中，这种平衡将在原子水平的细节使用量子力学（QM）和分子动力学（MD）的理论计算相结合的研究。为了实现这一目标，将进行经验力场的进一步发展，重点是改进目前可用的CHARMM 27加性模型和开发一种新的非加性力场，其中电子极化率通过经典的德鲁德振荡器显式处理。这些力场，通过MD模拟和潜在的平均力（PMF）的计算，将被用来确定环境的贡献RNA和DNA的属性，而QM计算将被用来确定内在的构象特性。待研究的生物系统包括DNA和RNA的各种典型形式以及包括凸起、发夹和RNA核糖开关的非典型形式。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。从这些调查原子的力量，稳定不同的构象的细节将得到。鉴于从这些研究中获得的见解，将阐明与其生物活性相关的DNA或RNA的构象特性。这些新发现最终将用于合理地靶向寡核苷酸，如核糖体和核糖开关，以创造新的抗生素。此外，在拟议的工作中开发的核酸更准确的经验模型将允许更现实的MD为基础的研究这些系统的理论化学和生物物理学社区。