Molecular Dynamics

项目摘要：核心 C – 分子动力学 (MD) 核心 这个 P01 项目探索了关于机械力的作用的几个新颖的概念和假设 T 细胞受体 (TCR) 库选择、抗原识别和信号生成。核心C执行 阐明原子层面的机制所必需的计算机模拟。由我们的支持 初步的实验和计算数据，Core C 的关键科学前提是 pre-TCR (pT - ) TCR 的功能不是静态结构，而是通过动态构象运动。特别是，我们 研究发现负载可以控制TCR不同域之间的相对运动，进而影响 抗原肽负载的主要组织相容性复合物 (pMHC) 结合界面的几何形状。小说 通过与试点项目的合作，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 关系，并识别机械响应域运动。测试是否符合建议的负载响应 机制是TCR特有的，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差。使用为 TCR 开发的计算方法，我们将 研究负载对 pT - 的影响。使用我们新发现的 X 射线结构代表进行初步模拟 对前 TCR-MHC 复合物的反感表明无肽 MHC 和 TCR 之间的结合界面 具有高度的动态性和移动性。我们假设结合的抗原肽和负载将使界面稳定成 配置适合 pT 阶段的曲目选择。将开发 Core C 中的模拟 通过与各个项目建立的强大反馈循环，利用来自光镊的数据（项目 1 和 2)、转录组（TCR 项目 1 和 pT - 项目 2）和 NMR（项目 3）。此外，在列 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 这将被实验测试。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。我们可以使用几台足以执行模拟的超级计算机 需要。

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.