Molecular Dynamics

项目摘要：核心C-分子动力学(MD)核心 这个P01项目探索了几个关于机械力的作用的新概念和假设 T细胞受体(TCR)谱系的选择、抗原识别和信号产生。核心C执行 在原子水平上阐明机制所必需的计算机模拟。由我们的 初步的实验和计算数据，核心C的关键科学fic前提是前Tcr(PT-) TCR不是作为静态结构发挥作用，而是通过动态构象运动发挥作用。特别是，我们 发现负载可以控制TCR不同区域之间的相对运动，进而影响TCR的 抗原肽负载的主要组织相容性复合体(PMHC)结合界面的几何形状。这部小说 该机制将通过与实验项目的合作进行进一步的测试和fi。我们的分析 包括：穷尽监测分子内和分子间的接触动力学，构象熵计算。 以及识别机械响应域的运动。测试建议的负载响应是否 TCR的机制是fic，我们将对功能不同的Tcr进行比较研究。 来自TCR，并且对负载的响应较小。使用为TCR开发的计算方法，我们将 研究负荷对PT-的影响。使用我们新发现的X射线结构代表进行了初步模拟。 反感前TCR-MHC复合体表明无肽MHC与TCR之间的结合界面 是高度动态和移动性的。我们假设结合的抗原肽和负载将把界面稳定到一个 CONfiGATION服从PT阶段的曲目选择。将开发核心C中的模拟 通过与个别项目建立的强反馈环路，利用来自光钳的数据(项目1 和2)、转录组(TCR的项目1和PT-的项目2)和核磁共振(项目3)。此外，在COLOR- 与Core B(蛋白质设计)合作，Core C将提供基于模拟的突变体和嵌合体设计 这将进行实验测试。将在蛋白质数据库中提供的结构上进行模拟 以及TCR和PT-的新结构，单独或与pMHC复合，将在 这个P01项目。我们可以访问几台超级计算机，这些计算机对执行模拟非常有效，例如 需要的。

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.