Molecular Dynamics

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.

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.