Elucidating Angular Protein Motion using Kinetic Ensemble Refinement
使用动力学系综细化阐明角蛋白运动
基本信息
- 批准号:10203376
- 负责人:
- 金额:$ 48.37万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-06-01 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingActive SitesAddressAdoptionAdvanced DevelopmentAffectAlgorithmsAllosteric RegulationAmino AcidsBenchmarkingBinding SitesBiologyBiophysical ProcessBiophysicsCatalysisChemicalsComputational TechniqueComputer ModelsComputer softwareCryoelectron MicroscopyCrystallizationCyclophilin ADataDevelopmentEnzymesExhibitsFoundationsGoalsIndividualKineticsKnowledgeLifeLigand BindingMeasuresMethodologyMethodsModelingMolecularMotionMovementMutagenesisNuclearNuclear Magnetic ResonanceNucleic Acid Regulatory SequencesPharmaceutical PreparationsPhysicsPositioning AttributeProcessProtein DynamicsProteinsProtocols documentationPublic HealthResearchSideStructureTechniquesTemperatureTestingTherapeuticTranslatingUncertaintyValidationVertebral columnWorkX-Ray Crystallographyactive methodbasecare outcomescrystallinitydesigndrug developmentexhaustionexpectationexperimental studyimprovedmolecular modelingmulti-scale modelingnovel strategiesnovel therapeuticsnuclear Overhauser enhancementprogramsprotein functionprotein structurerestraintstructural biologytool
项目摘要
PROJECT SUMMARY/ABSTRACT
To advance the understanding of atomic-level mechanisms behind critical protein functions like enzyme
catalysis and allosteric regulation, it is important to first elucidate a true representation of the protein in
solution. In an effort to achieve this long term goal, we will use the recently developed Kinetic Ensemble
approach to transform the way in which nuclear magnetic resonance (NMR) data is computationally modeled
to solve protein structures and measure protein motions. NMR is one of the most powerful techniques for
elucidating the structure and dynamics of proteins. It enables their study in solution (unlike x-ray
crystallography) and can capture critical structural rearrangements as they happen at room temperature (unlike
cryo-electron microscopy). However, despite these advantages, there have been relatively few practical
improvements to one of the foundational aspects behind the way protein structures are solved, namely the
calculation of interatomic distances from nuclear Overhauser effect (NOE) experiments. Such methods have
remained largely qualitative, resulting in large uncertainties in the atomic positions for most NMR structures.
Also, the field has almost completely ignored how angular motion and kinetics affect the NOE, resulting in
atoms appearing much further away from one another than they actually are. To overcome these significant
deficiencies, we will implement and test new Kinetic Ensemble-based refinement algorithms that are
considerably more accurate and physically realistic than previous approaches, accounting for both angular
motion and kinetics. To eliminate a significant fraction of the systematic and random structural errors resulting
from poorly quantified NMR spectra, we will also integrate advances made by the FitNMR peak quantification
software recently developed by our lab. These methods will be used to create better experimental NMR
structures, more exhaustive models of side chain dynamics, and determine differences between solution and
crystal states with unprecedented detail. This work will allow much more accurate determination of the
structural dynamics in parts of the protein exhibiting significant fluctuations, including protein active sites,
regulatory regions, and hidden binding sites. Such knowledge will advance our fundamental understanding of
protein biophysics and facilitate rational design of new therapeutics.
项目概要/摘要
促进对酶等关键蛋白质功能背后的原子级机制的理解
催化和变构调节,首先阐明蛋白质的真实代表非常重要
解决方案。为了实现这一长期目标,我们将使用最近开发的 Kinetic Ensemble
改变核磁共振 (NMR) 数据计算建模方式的方法
解决蛋白质结构并测量蛋白质运动。 NMR 是最强大的技术之一
阐明蛋白质的结构和动力学。它使他们能够在溶液中进行研究(与 X 射线不同)
晶体学)并且可以捕获在室温下发生的关键结构重排(与
冷冻电子显微镜)。然而,尽管有这些优点,但实际应用的还相对较少。
对蛋白质结构解决方式背后的基本方面之一的改进,即
根据核奥沃豪瑟效应 (NOE) 实验计算原子间距离。此类方法有
很大程度上仍然是定性的,导致大多数 NMR 结构的原子位置存在很大的不确定性。
此外,该领域几乎完全忽略了角运动和动力学如何影响 NOE,从而导致
原子之间的距离看起来比实际距离远得多。为了克服这些重大
缺陷,我们将实施和测试新的基于动力学集成的细化算法,这些算法是
比以前的方法更加准确和物理真实,考虑了角度
运动和动力学。消除所产生的系统和随机结构误差的很大一部分
针对量化不佳的 NMR 谱,我们还将整合 FitNMR 峰量化取得的进展
我们实验室最近开发的软件。这些方法将用于创建更好的实验核磁共振
结构,更详尽的侧链动力学模型,并确定解决方案和
具有前所未有的细节的晶体状态。这项工作将能够更准确地确定
蛋白质部分的结构动力学表现出显着的波动,包括蛋白质活性位点,
调节区域和隐藏的结合位点。这些知识将增进我们对以下问题的基本理解:
蛋白质生物物理学并促进新疗法的合理设计。
项目成果
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相似海外基金
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毒素纳米孔结构动力学的分子分析
- 批准号:
9095733 - 财政年份:2016
- 资助金额:
$ 48.37万 - 项目类别: