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Fast model systems for misfolding, binding and aggregation

用于错误折叠、绑定和聚合的快速模型系统

基本信息

批准号：
8578400
负责人：
MARTIN GRUEBELE
金额：
$ 30.55万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8578400
关键词：
Adult Amyloid Amyloidosis Binding Binding Proteins Binding Sites Biological Models Chimera organism Communities Complement Complex Computers Coupled Data Deglutition Development Device or Instrument Development Diffusion Disease Dissociation Elements Engineering Equilibrium Event Experimental Models Eyelid structure Feedback Free Energy Future Generations Goals Grant Illinois Kinetics Knowledge Lasers Learning Measures Micelles Mining Modeling Mutation Nucleic Acids Pathway interactions Plant Roots Population Postdoctoral Fellow Process Proteins RNA RNA Binding RNA-Binding Proteins Reaction Relaxation Relaxation Techniques Research Resolution Signal Transduction Site Solutions Sorting - Cell Movement Speed Structure Students System Technology Time U1A protein United States National Institutes of Health Visit Work base crosslink improved instrument interest intermolecular interaction meetings millisecond molecular dynamics monomer next generation protein aggregation protein folding prototype public health relevance research study simulation single molecule success supercomputer temperature jump

项目摘要

DESCRIPTION (provided by applicant): Fast (microsecond) experiments and molecular dynamics simulation are finally working hand-in-hand to provide validated atomistic pictures of protein folding dynamics. Larger proteins and millisecond folders are around the corner, although empirical force fields need more improvement before mechanistic predictions become as reliable as average rate coefficients or native structures. It is time to extend this simulation experiment interplay to misfolding, aggregation and binding processes. The problem is that such processes are usually slow - seconds to days. In order to compare experiment and simulation directly during the next 4 years, when simulations will not reach far beyond the 1 ms regime yet, the solution is simple: create small and fast experimental model systems for misfolding, aggregation and binding. These are analogous to fast two-state and downhill folding studied during the last 10 years: certainly not all proteins fold that way, but much useful was learned from our ability to directly compare such model proteins with simulation. Here, we propose development of: 1) ?6-85 as a model system for sheet-containing misfolded traps (T denaturation and T-jumps) as well as excess helix-containing traps (P denaturation, P-jumps). The key is that all folding and misfolding events are completed in ~ 1 ms or faster. 2a) Fast-folding tethered proteins (WW and ?6-85) to facilitate the interplay between transient aggregation and folding. Oligomeric aggregates include chimeras with elements swapped among monomers, as well as less structured aggregates. Tethering allows high effective concentrations without going to high protein concentration (leading to uncontrollable aggregation), and also helps keep MD simulation by keeping reactants in close proximity. 2b) U1A-RNA binding to multiple sites on U1A protein will be a fast model system for binding at multiple sites. 3) For the next generation of misfolding/aggregation/binding research, we will develop a single molecule instrument capable of high throughput (106 molecules/day) and studying 2 or more molecules interacting without cross-linking them or confining them in a micelle. Five simulation groups have been brought on board (Schulten, Shaw, Cheung, Luthey-Schulten and Pande), and their students/postdocs are already working closely with mine so simulation can be developed in parallel with the experiments. The goal is to provide data in the few microsecond to few millisecond range, amenable to full atom simulation over the next 4 years, so misfolding/aggregation/binding processes can be studied at the atomistic level, but on systems small and fast enough for simulation to work. We build on our knowledge of ?6-85, WW domain and U1A, so much is known experimentally and computationally about the monomeric building blocks of our misfolding/aggregation/binding models.

描述（由申请人提供）：快速（微秒）实验和分子动力学模拟最终携手提供蛋白质折叠动力学的验证原子图像。更大的蛋白质和毫秒级的文件夹即将问世，尽管在机械预测变得像平均速率系数或天然结构一样可靠之前，经验力场还需要更多的改进。是时候扩展这个模拟了