Molecular Dynamics
Molecular Dynamics
批准号:
10655326
负责人:
Wonmuk Hwang
金额:
$14.14万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
未结题
起止时间:
2020-07-29 至 2025-06-30
关键词:
AffectAntigensBehaviorBindingBiologyCell LineageChimera organismCollaborationsComparative StudyComplexComputer SimulationComputer-Aided DesignDataDevelopmentEffectivenessEntropyEvolutionExhibitsFeedbackGenerationsGeometryGoalsIndividualLinkLogisticsMajor Histocompatibility ComplexMeasurementMechanicsMethodsModelingMolecular ConformationMonitorMotionPeptidesPrincipal Component AnalysisPropertyProtein EngineeringResourcesRoentgen RaysRoleSideSignal TransductionSpecific qualifier valueSpecificityStructural ModelsStructureSurfaceSystemT-Cell ReceptorT-LymphocyteT-cell receptor repertoireTechniquesTestingTimeVertebral columndesignexperienceexperimental studyinsightlaser tweezermechanical forcemolecular dynamicsmutantnext generation sequencingnoveloptic tweezerpeptide structureprotein data bankreceptor functionresponsesimulationsingle moleculesupercomputertranscriptometranscriptome sequencing
中文摘要
项目概要:Core C -分子动力学(MD)Core
这个P01项目探讨了几个关于机械力作用的新概念和假设,
T细胞受体(TCR)库选择、抗原识别和信号产生。核心C执行
计算机模拟是必要的,以阐明在原子水平的机制。支持我们的
根据初步的实验和计算数据,核心C的关键科学前提是前TCR(pT -)
TCR不是静态结构,而是经历动态构象运动。我们尤其
已经发现,负载可以控制TCR不同域之间的相对运动,这反过来又影响TCR的功能。
装载抗原肽的主要组织相容性复合物(pMHC)结合界面的几何形状。小说
将通过与实验项目的合作进一步测试和完善该机制。我们的分析
包括:分子内和分子间接触动力学的详尽监测,构象熵计算,
定位和识别机械响应域运动。为了测试所提出的载荷响应是否
由于TCR的机制是特异性的,我们将对功能不同的TCR进行比较研究。
从TCR,并对负载的响应较小。使用TCR开发的计算方法,我们将
研究负荷对pT -的影响。初步模拟使用我们新发现的x射线结构代表-
呈现前TCR-MHC复合物表明无肽MHC和TCR之间的结合界面
是高度动态和移动的。我们认为,结合的抗原肽和负载将使界面稳定成一个稳定的界面。
在pT -阶段,该构型适合于库选择。将开发Core C中的模拟
通过与各个项目建立的强反馈回路,利用来自光镊的数据(项目1
和2)、转录组(TCR的项目1和pT -的项目2)和NMR(项目3)。此外,在Col-
核心B(蛋白质设计),核心C将提供基于模拟的突变体和嵌合体设计
这将通过实验进行测试。将对蛋白质数据库中可用的结构进行模拟
以及TCR和pT -的新结构,单独或与pMHC复合,这将在
P01项目我们可以使用几台超级计算机,这些计算机足以进行模拟,
needed.
英文摘要
Project Summary: Core C – Molecular Dynamics (MD) Core
This P01 project explores several novel concepts and hypotheses regarding the role of mechanical force for
the T-cell receptor (TCR) repertoire selection, antigen recognition, and signal generation. Core C carries out
computer simulations that are necessary to elucidate the mechanisms at the atomistic level. Supported by our
preliminary experimental and computational data, the key scientific premise of Core C is that pre-TCR (pT - )
and TCR function not as static structures, but by undergoing dynamic conformational motion. In particular, we
have found that load can control the relative motion between different domains of TCR, which in turn affect the
geometry of the antigenic peptide-loaded major histocompatibility complex (pMHC) binding interface. The novel
mechanism will be further tested and refined through collaboration with experimental projects. Our analyses
include: exhaustive monitoring of intra- and inter-molecular contact dynamics, conformational entropy calcu-
lation, and identifying mechanically responsive domain motion. To test whether the proposed load-response
mechanism is specific for TCR , we will carry out comparative studies of TCR that is functionally different
from TCR and is less responsive to load. Using the computational approaches developed for TCR , we will
investigate the effect of load on pT - . Preliminary simulation using our newly discovered x-ray structure rep-
resenting a preTCR-MHC complex indicates that the binding interface between a peptide-free MHC and TCR
is highly dynamic and mobile. We posit that a bound antigenic peptide and load will stabilize the interface into a
configuration amenable to the repertoire selection at the pT - stage. Simulations in Core C will be developed
through strong feedback loops established with individual projects, utilizing data from optical tweezers (Project 1
and 2), transcriptome (Project 1 for TCR and Project 2 for pT - ), and NMR (Project 3). Furthermore, in col-
laboration with Core B (Protein Design), Core C will provide simulation-based design of mutants and chimeras
that will be experimentally tested. Simulations will be performed on structures available in Protein Data Bank
as well as new structures of TCR and pT - , individually or complexed with pMHC, that will be solved in
this P01 project. We have access to several supercomputers that are sufficient for performing simulations as
needed.
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专著(0)
科研奖励(0)
会议论文
Molecular Dynamics
-
批准号:10438677
-
项目类别:
-
资助金额:$13.1万
-
财政年份:2020
-
负责人:Wonmuk Hwang
-
依托单位:
Molecular Dynamics
-
批准号:10020599
-
项目类别:
-
资助金额:$15.03万
-
财政年份:2020
-
负责人:Wonmuk Hwang
-
依托单位:
Molecular Dynamics
-
批准号:10225506
-
项目类别:
-
资助金额:$12.45万
-
财政年份:2020
-
负责人:Wonmuk Hwang
-
依托单位:
THE ATOMISTIC SCALE KINESIN MECHANISM ELUCIDATED ON THE EXPERIMENTAL TIME SCALE
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批准号:8364330
-
项目类别:
-
资助金额:$0.11万
-
财政年份:2011
-
负责人:Wonmuk Hwang
-
依托单位:
Computational and single molecule analysis of kinesin's atomistic machinery
-
批准号:8330273
-
项目类别:
-
资助金额:$22.26万
-
财政年份:2009
-
负责人:Wonmuk Hwang
-
依托单位:
Computational and single molecule analysis of kinesin's atomistic machinery
-
批准号:8134974
-
项目类别:
-
资助金额:$22.3万
-
财政年份:2009
-
负责人:Wonmuk Hwang
-
依托单位:
Computational and single molecule analysis of kinesin's atomistic machinery
-
批准号:7920016
-
项目类别:
-
资助金额:$22.56万
-
财政年份:2009
-
负责人:Wonmuk Hwang
-
依托单位:
Computational and Single-Molecule Characterization of Kinesin's Power Stroke
-
批准号:7357447
-
项目类别:
-
资助金额:$18.59万
-
财政年份:2007
-
负责人:Wonmuk Hwang
-
依托单位:
Computational and Single-Molecule Characterization of Kinesin's Power Stroke
-
批准号:7241336
-
项目类别:
-
资助金额:$16.91万
-
财政年份:2007
-
负责人:Wonmuk Hwang
-
依托单位:
国内基金
海外基金
Neo-antigens暴露对肾移植术后体液性排斥反应的影响及其机制研究
-
批准号:2022J011295
-
项目类别:省市级项目
-
资助金额:10.0万元
-
批准年份:2022
-
负责人:王亚伟
-
依托单位:
结核分枝杆菌持续感染期抗原(latency antigens)的重组BCG疫苗研究
-
批准号:30801055
-
项目类别:青年科学基金项目
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资助金额:19.0万元
-
批准年份:2008
-
负责人:王丽梅
-
依托单位: