QM-MM PREDICTIONS OF PHOTOINDUCED ELECTRON TRANSFER IN PROTEINS

蛋白质中光诱导电子转移的 QM-MM 预测

• 批准号: 8171930
• 负责人: PATRIK R CALLIS
• 金额: $ 0.11万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8171930
• 关键词: Area; Behavior; Biological; Computer Retrieval of Information on Scientific Projects Database; Coupled; Coupling; Electron Transport; Electrostatics; Elements; Environment; Enzymes; Fluorescence; Funding; Grant; Heterogeneity; Hydration status; Institution; Measurement; Monitor; Positioning Attribute; Property; Protein Conformation; Proteins; Relaxation; Research; Research Personnel; Resources; Solvents; Source; Students; Time; Tryptophan; United States National Institutes of Health; Variant; Work; electric field; millisecond; protein folding; protein structure; research study; simulation; single molecule; villin

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We request resources to enable significantly more realistic QM-MM computations that aim to explore the extremely rugged electrostatic landscape of proteins through a detailed fundamental understanding of two phenomena that are widely exploited to study protein structure and dynamics: tryptophan (Trp) fluorescence quenching (by electron transfer from the excited state) and tryptophan fluorescence wavelength shifts due to hydration of the large excited state dipole. Particular focus during the next three years will be on (1) understanding ultrafast (0.5 -100 ps) fluorescence intensity decay (quenching) and wavelength shift experiments on proteins, (2) the spectacular fluctuation of quenching rates seen in single-molecule fluorescence of proteins, and (3) the underlying mechanisms of quenching variation used to monitor protein folding. These are areas of cutting edge experimental work. The project builds on 9 previous years of NSF support for mostly computational work that led to unprecedented progress in understanding Trp fluorescence wavelength variability in proteins using electrostatics, and to unprecedented progress in understanding of the previously unexplained--but widely exploited--Trp fluorescence intensity changes accompanying changes in protein structure. This work has recently been funded by NSF (NSF Proposal ID: 0847047) for the period Aug 2009-July 2012. Our recent ab initio computations of realistic electron transfer coupling elements during dynamics simulations led unexpectedly to an understanding of why wavelength and quenching are often strongly coupled and correlated. With the aid of the proposed multiple ns-scale simulations, the project is now immediately in a position to make insightful contributions to the contested notion that time resolved wavelength shifts speak solely to solvation dynamics, rather than a mixture of solvation dynamics and long term heterogeneity in protein conformation. This is particularly relevant to items (1) and (2) above. A constant theme of our work has shown the supreme importance of the enormous local electric field strength and direction in determining fluorescence behavior in proteins. Continued effort in these areas is encouraged by the emerging view that the catalytic power of enzymes is largely due to a specifically oriented, preorganized electrostatic environment, whose energy may come from reduction in folding energy. A constant theme from the Callis group has been that an ordered electrostatic environment coupled with large fluctuations is precisely what determines whether fluorescence will be strong or weak, and whether its average wavelength will be short or long. This meshes perfectly with the exciting recent observation by Marcus and others that the temporal behavior of fluctuations in electrostatic field is in common with that of other properties of proteins over the time scale of biological importance (milliseconds to seconds). Two students and a postdoctoral associate will work on subprojects entitled: (A) QM-MM simulations examining the relationship of solvent relaxation and heterogeneity in ultrafast TDSS measurements, and (B) Prediction of tryptophan fluorescence intensities during folding of the villin headpiece. The PI requests 500, 000 SU.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 We request resources to enable significantly more realistic QM-MM computations that aim to explore the extremely rugged electrostatic landscape of proteins through a detailed fundamental understanding of two phenomena that are widely exploited to study protein structure and dynamics: tryptophan (Trp) fluorescence quenching (by electron transfer from the excited state) and tryptophan fluorescence wavelength shifts due to hydration of the large excited state dipole.在接下来的三年中，特别的重点将放在（1）理解蛋白质上的超快（0.5 -100 PS）荧光强度衰减（淬火）和波长转移实验，（2）在蛋白质的单分子荧光中看到的震荡速率的壮观波动，以及（3）使用Quench蛋白质的基础机制。这些是尖端实验工作的领域。该项目建立在NSF的9个持续几年支持的基础上，主要是计算工作，这在理解蛋白质中使用静电仪的蛋白质中的前所未有的进展，以及在理解以前未被解释的 - 广泛利用的 - trp荧光强度变化的蛋白质结构变化方面的前所未有的进展。这项工作最近由NSF（NSF提案ID：0847047）在2009年8月至2012年的2012年。我们最近对动态模拟期间现实电子传输耦合元件的近期开始计算出乎意料地理解了为什么波长和Quenching和Quenching频率经常被强烈搭配和相关。借助拟议的多个NS尺度模拟，该项目现在立即有能力对有争议的观念做出深刻的贡献，即时间解决波长的变化仅代表溶剂化动力学，而不是溶剂化动力学和长期异质性在蛋白质构象中的混合。这与上述项目（1）和（2）尤其相关。我们工作的一个恒定主题表明，局部电场强度和确定蛋白质荧光行为的最高重要性。新兴观点鼓励在这些地区继续努力，即酶的催化能力在很大程度上是由于特定定向的，预组织的静电环境，其能量可能来自减少折叠能量的能量。 Callis组的一个恒定主题是，有序的静电环境加上大波动，正是决定荧光是强还是弱的，以及其平均波长是短还是长的。这与马库斯（Marcus）以及其他人最近观察到的令人兴奋的观察结果与静电场中波动的时间行为与蛋白质的其他特性（在生物学重要性的时间尺度上（毫秒至几秒钟））具有共同点。两名学生和一名博士后助理将致力于题为：（a）QM-MM模拟在超快TDSS测量中检查溶剂放松和异质性的关系，以及（b）在Villin Headpiece折叠期间的色氨酸荧光强度预测。 PI请求500，000 su。