Exploring RNA Folding and Dynamics Using a Polarizable Force Field

使用极化力场探索 RNA 折叠和动力学

• 批准号: 8645182
• 负责人: Justin Alan Lemkul
• 金额: $ 5.15万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8645182
• 关键词: 5' Untranslated Regions; Accounting; Address; Adoption; Alphaproteobacteria; Anabolism; Antibiotics; Area; Bacteria; Binding; Biology; Catalysis; Catalytic RNA; Cell physiology; Cells; Charge; Complex; Coupled; Cystic Fibrosis; Data; Development; Disease; Distal; Electronics; Equilibrium; Event; Free Energy; Gene Expression; Gene Expression Regulation; Goals; Growth; Hydration status; Hydrogen Bonding; Investigation; Ions; Kinetics; Lead; Ligand Binding; Light; Malignant Neoplasms; Messenger RNA; Metabolism; Metal Ion Binding; Metals; Methionine; Methodology; Methods; MicroRNAs; Modeling; Molecular; Molecular Conformation; Mutation; Nucleic Acids; Parkinsonian Disorders; Pathway interactions; Process; Proteins; Quantum Mechanics; RNA; RNA Folding; RNA Sequences; RNA Stability; Radial; Regulation; Research; Resolution; Ribosomal RNA; Role; S-Adenosylmethionine; Sampling; Simulate; Small RNA; Solvents; Structure; Sulfur Metabolism Pathway; Surface; System; Thermodynamics; Time; Transfer RNA; Translating; Work; base; design; driving force; human disease; improved; insight; macromolecule; molecular dynamics; molecular mechanics; novel; polyanion; public health relevance; research study; simulation; small molecule; solute; tool

DESCRIPTION (provided by applicant): The goals of the proposed research are to (1) to derive a set of suitable atomic radii for use in continuum dielectric Poisson-Boltzmann (PB) and solvent accessibility (SA) implicit solvent calculations within the context of a Drude polarizable force field and (2) apply this extended PB-polarizable force field treatment to RNA molecules of increasing complexity to quantify the driving forces for RNA folding, stability, and dynamics. The overarching objective is to study RNA folding by quantifying the free energy differences between conformational states and thus describe folding pathways for RNA in a quantitative manner. The PB/SA methodology could also be used in protein simulations. Simulations of RNA folding will be conducted using enhanced sampling methods to investigate folded, unfolded, and intermediate states of RNA molecules with various features (hairpins, pseudoknots, etc). Free energies from the MM/PBSA calculations will be coupled with information on base stacking energetics from quantum mechanics (QM) calculations to obtain a quantitative molecular understanding of events occurring during RNA folding. This information is important not only from a fundamental standpoint of understanding RNA folding, but also due to the fact that mutations in RNA that cause misfolding often lead to disease. In addition, studies on the SAM-II riboswitch, which binds S-adenosylmethionine (SAM) in bacteria, will be used to quantitatively describe the differences in apo- and SAM-bound configurations. Since many bacterial species use riboswitches to control gene expression, the proposed studies will provide information that can be used in the development of novel antibiotics. Polarizable force fields are especially relevant in these studies since the conformations of the strongly charged RNA molecules are highly dynamic and dependent upon metal binding. The three Aims described in this project are: 1. Extend the existing Drude polarizable force field to include parameters for MM/PBSA calculations. The use of MM/PBSA calculations allows for accurate estimates of free energies of macromolecular configurations. Atomic radii for MM/PBSA calculations will be tuned based on free energies of solvation from FEP and experiments. 2. Quantitate the effect of polarization on the folding and stabilization of small RNA molecules. RNA folding pathways are complex, and driving forces are not completely understood. Using enhanced sampling methods in conjunction with MM/PBSA and QM calculations, we will quantitate the role of polarization and metal binding on the folding pathway(s) of small RNA molecules. 3. Investigate the dynamics and free energy between conformational states of the SAM-II riboswitch. Riboswitch function depends on conformational changes induced by metabolite binding. In this Aim, we will investigate the driving forces behind these binding events and the resulting conformational changes.

描述（由申请人提供）：拟议研究的目标是（1）导出一组合适的原子半径，用于连续介质泊松-玻尔兹曼（PB）和溶剂可及性（SA）隐式溶剂计算Drude 极化力场；(2) 将这种扩展的 PB 极化力场处理应用于复杂性不断增加的 RNA 分子，以量化 RNA 折叠、稳定性和动力学的驱动力。总体目标是通过量化构象状态之间的自由能差异来研究 RNA 折叠，从而以定量方式描述 RNA 的折叠途径。 PB/SA 方法也可用于蛋白质模拟。将使用增强采样方法进行 RNA 折叠模拟，以研究具有各种特征（发夹、假结等）的 RNA 分子的折叠、展开和中间状态。来自 MM/PBSA 计算的自由能将与来自量子力学 (QM) 计算的碱基堆积能量学信息相结合，以获得对 RNA 折叠过程中发生的事件的定量分子理解。这些信息不仅从理解 RNA 折叠的基本角度来看很重要，而且还因为导致错误折叠的 RNA 突变通常会导致疾病。此外，对细菌中结合 S-腺苷甲硫氨酸 (SAM) 的 SAM-II 核糖开关的研究将用于定量描述 apo 和 SAM 结合构型的差异。由于许多细菌物种使用核糖开关来控制基因表达，因此拟议的研究将提供可用于开发新型抗生素的信息。极化力场在这些研究中尤其重要，因为带强电荷的 RNA 分子的构象是高度动态的并且依赖于金属结合。该项目描述的三个目标是： 1. 扩展现有的 Drude 极化力场以包括 MM/PBSA 计算的参数。使用 MM/PBSA 计算可以准确估计大分子构型的自由能。 MM/PBSA 计算的原子半径将根据 FEP 和实验的溶剂化自由能进行调整。 2. 定量极化对小 RNA 分子折叠和稳定的影响。 RNA 折叠途径很复杂，驱动力尚未完全了解。使用增强采样方法结合 MM/PBSA 和 QM 计算，我们将量化极化和金属结合对小 RNA 分子折叠途径的作用。 3. 研究 SAM-II 核糖开关构象状态之间的动力学和自由能。核糖开关功能取决于代谢物结合诱导的构象变化。在这个目标中，我们将研究这些结合事件背后的驱动力以及由此产生的构象变化。