Biomolecular folding by ultrafast spectroscopy and high performance computing

通过超快光谱和高性能计算进行生物分子折叠

• 批准号: 7409385
• 负责人: JEFFREY D EVANSECK
• 金额: $ 5.5万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7409385
• 关键词: Affect; Attention; Back; Base Pairing; Behavior; Biochemical; Biochemistry; Biological; California; Charge; Chickens; Code; Collaborations; Coumarins; DNA; DNA Folding; Data; Development; Discipline; Disease; Dissection; Dyes; Educational process of instructing; Environment; Event; Fluorescence; Fluorescence Resonance Energy Transfer; Frustration; Funding; Goals; Health; Heating; Helix (Snails); High Performance Computing; Imagery; Institutes; Intention; Ions; Joints; Kinetics; Laboratories; Lasers; Leucine; Measurement; Measures; Mediating; Medical; Methodology; Methods; Microscopic; Modeling; Molecular Conformation; Molecular Structure; Monitor; Motion; Mutation; Names; Numbers; Oligonucleotides; Phenylalanine; Physical Chemistry; Placement; Play; Positioning Attribute; Principal Component Analysis; Process; Proteins; Publications; Quality Control; Range; Rate; Reaction; Relaxation; Reporting; Research; Research Personnel; Role; Scientist; Site; Slave; Solvents; Spectrum Analysis; Staging; Stress; Structure; System; Technology; Testing; Time; Training; Tryptophan; Universities; Water; Work; alpha benzopyrone; analog; base; career; design; ear helix; experience; field study; interest; large scale simulation; melting; molecular dynamics; professor; programs; protein folding; protein misfolding; protein structure; research study; response; simulation; size; stem; villin

DESCRIPTION (provided by applicant): The broad, long-term objective of the proposed collaborative research is to articulate a microscopic basis for biomolecular folding codes. Recent tantalizing data from ultrafast T-jump experiments reported on proteins and DNA demonstrate the importance of separating events on the ultrashort time scale for solvation and folding. Data from ultrafast spectroscopy and multiple large-scale explicit water simulations will be interpreted with principal component analysis to provide a fresh perspective to the field. Our interest is in the relationship between water configurations and biomolecular structural change that occurs in less than the 100 picosecond regime. The immediate objective, however, is to examine the role of water in early folding events that may guide (slave) hydrophobic collapse to the native structure of proteins and DMA. Specific Aim 1: Initial water events for the folding of chicken villin headpiece subdomain. The fastest known ultrafast folding sequence, chicken villin headpiece subdomain (35-residues, VHS), will be studied using ultrafast experiments and computational all-atom simulations to provide a microscopic interpretation of folding. We propose to pay particular attention to the effects of solvent. Despite the extensive experimental and theoretical work reported on VHS, critical issues surrounding a microscopic understanding remain unanswered. Specific Aim 2: Construct a microscopic understanding of DNA folding and melting of a hairpin structure. The folding and melting kinetics of a 25 residue oligonucleotide hairpin structure has been reported using an ultrafast T-jump method. Three real-time events have been observed to include the timescales of water heating (<20 ps), double-strand destacking (700 ps to 2 ns), and loss of hairpin structure (greater than or equal to us). This experimental data has motivated us to pursue a microscopic interpretation to the role of water and ions on the three-state picture of melting and folding proposed by experiment. Public Statement: Advances in understanding how biological structures "fold" or attain their biochemical functional form will allow scientists and medical doctors cure diseases never considered possible before.

描述（由申请人提供）：拟议的协作研究的广泛长期目标是阐明生物分子折叠代码的显微镜基础。从超快T突变实验中报告的蛋白质和DNA的最新诱人数据表明，在超短时间尺度上分离事件以进行溶剂化和折叠的重要性。超快光谱和多个大规模显式水模拟的数据将通过主成分分析来解释，以为该领域提供新的视野。我们的兴趣是水构型与小于100秒制度的生物分子结构变化之间的关系。然而，直接的目标是检查水在早期折叠事件中的作用，这些事件可能引导（奴隶）疏水性塌陷到蛋白质和DMA的天然结构。特定目标1：鸡肉villin头饰子域的折叠的初始水事件。将使用Ultrafast实验和计算全部原子模拟来研究最快的已知超快折叠序列，即鸡肉villin头饰子域（35个分散，VHS），以提供折叠的微观解释。我们建议特别注意溶剂的影响。尽管报道了有关VHS的广泛实验和理论工作，但围绕微观理解的关键问题仍未得到解答。特定目标2：构建对发夹结构的DNA折叠和熔化的微观理解。使用超快速T-JUMP方法据报道了25个残基寡核苷酸发夹结构的折叠和熔化动力学。已经观察到三个实时事件包括水加热的时间尺度（<20 ps），双链破坏（700 ps至2 ns）以及发夹结构的丢失（大于或等于我们）。该实验数据促使我们对水和离子在实验提出的熔化和折叠的三态图中的作用进行微观解释。 公开声明：了解生物结构如何“折叠”或获得其生化功能形式的进步将使科学家和医生治愈以前从未考虑过的疾病。