Biomolecular folding by ultrafast spectroscopy and high performance computing

描述（由申请人提供）：拟议的合作研究的广泛，长期目标是阐明生物分子折叠代码的微观基础。最近从蛋白质和DNA的超快T-跳跃实验报告的诱人的数据证明了在超短时间尺度上分离溶剂化和折叠事件的重要性。来自超快光谱和多个大规模显式水模拟的数据将用主成分分析进行解释，为该领域提供新的视角。我们的兴趣是在水的配置和生物分子的结构变化，发生在小于100皮秒制度之间的关系。然而，当前的目标是研究水在早期折叠事件中的作用，这些事件可能会引导（奴隶）疏水性崩溃到蛋白质和DMA的天然结构。具体目标1：鸡绒毛蛋白头片段亚结构域折叠的初始水事件。已知最快的超快折叠序列，鸡绒毛头部亚域（35个残基，VHS），将研究使用超快实验和计算全原子模拟，以提供折叠的微观解释。我们建议特别注意溶剂的影响。尽管广泛的实验和理论工作报道的VHS，围绕微观理解的关键问题仍然没有答案。具体目标2：构建对DNA折叠和发夹结构解链的微观理解。使用超快T-跳跃方法报道了25个残基的寡核苷酸发夹结构的折叠和解链动力学。已经观察到三个实时事件，包括水加热的时间尺度（<20 ps）、双链解堆（700 ps至2 ns）和发夹结构的损失（大于或等于us）。这些实验数据促使我们对水和离子在实验提出的熔化和折叠三态图像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展将使科学家和医生能够治愈以前从未考虑过的疾病。

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.