Structural biophysics and molecular design in cellular immunity

摘要 我们由NIGMS资助的研究强调结构生物学、分子生物物理学和 免疫学。从广义上讲，我们的目标是将支配蛋白质的基本物理原理联系起来 免疫系统中具有功能的行为，依赖于生物物理学、结构学中的各种方法 生物学、计算生物化学和分子免疫学。除了提供机械的洞察力之外 免疫学，我们在这个界面上的工作对于解决生物分子的基本规则是有指导意义的 识别和其他蛋白质行为，以及复杂系统的建模和设计。在这 关于续签，我们建议继续这一跨学科的重点。我们的研究强调T细胞受体(TCR)和 它们的配体，由主要组织相容性复合体蛋白(肽/MHC)结合和呈现的短肽 复合体)。TCR识别多肽/MHC复合体是细胞免疫的基石，因为它定义了 特异性，并启动信号，导致T细胞免疫反应。由于两者都有很高的多样性 受体和配体，以及这些分子参与的无数过程，TCRs- 多肽/MHC相互作用被认为是生物学中最复杂的相互作用之一。解构如何具体化 面对这种异常复杂的情况，学习如何预测和操作TCR识别 特性和理解T细胞信号传递过程的生物物理学仍然是我们研究的核心。 我们的动力不仅来自于获得进一步机械洞察的渴望，也来自于新技术的发展 基因工程T细胞和基于多肽的疫苗等治疗方法。虽然已经有了 在免疫治疗取得成功的同时，也出现了严重的并发症和令人困惑的结果。它是 人们普遍认为，需要更好地理解免疫识别的基本原理 这样的疗法才能发挥其潜力。我们今后五年的目标包括提高对 TCR交叉反应和特异性的机制，最终目的是利用结构信息和 用于识别交叉反应配体的建模。在这方面的进步将需要相应地提高我们的能力 对蛋白质-蛋白质界面进行建模和评分，这是 我们的关注点。我们还计划评估TCR-肽/MHC界面中神秘的“捕获键”的机制 通过物理化学的镜头，这一观点在捕获键的讨论中基本上没有 在免疫学方面。我们的目标也是将物理化学和结构生物学的元素引入预测 免疫原性，通过考虑蛋白质-蛋白质分子识别的生物物理学来解决这个问题。最后，我们 目的继续我们在动态变构方面的工作，研究蛋白质动力学如何有助于免疫识别 以及仍然知之甚少的T细胞触发机制。我们的工作仍然高度协作， 跨学科，使其能够影响分子和细胞免疫学以及蛋白质生物物理学的多个领域。

Abstract Our NIGMS-funded research emphasizes the interface between structural biology, molecular biophysics, and immunology. Broadly speaking, we aim to connect the fundamental physical principles that govern protein behavior with function in the immune system, relying on a wide variety of approaches in biophysics, structural biology, computational biochemistry, and molecular immunology. In addition to providing mechanistic insight into immunology, our work in this interface has been instructional for addressing basic rules of biomolecular recognition and other protein behavior, as well as in the modeling and design of complex systems. In this renewal, we propose to continue this interdisciplinary focus. Our studies emphasize T cell receptors (TCRs) and their ligands, short peptides bound and “presented” by major histocompatibility complex proteins (peptide/MHC complexes). TCR recognition of peptide/MHC complexes is the cornerstone of cellular immunity, as it defines specificity and initiates the signaling that leads to T cell immune responses. Owing to the high diversity in both receptor and ligand, as well as the myriad of processes in which these molecules participate, the TCRs- peptide/MHC interaction is recognized as one of the most complex in biology. Deconstructing how specificity emerges in the face of this extraordinary complexity, learning how to predict and manipulate TCR recognition properties, and understanding the biophysics of T cell signaling processes remains at the core of our studies. We are motivated not only by the desire to gain further mechanistic insight, but also by the growth of new therapeutic approaches such as gene-engineered T cells and peptide-based vaccines. While there have been immunotherapy successes, there have also been significant complications and confounding outcomes. It is widely understood that an improved understanding of the fundamentals of immune recognition is needed for such therapies to reach their potential. Our goals for the next five years include improving our understanding of the mechanisms of TCR cross-reactivity and specificity, with an eventual goal of using structural information and modeling to identify cross-reactive ligands. Advances here will require concomitant improvements in our ability to model and score suboptimal (or as we call them, “sloppy”) protein-protein interfaces, which is a major part of our focus. We also plan to assess the mechanism of enigmatic “catch bonds” in TCR-peptide/MHC interfaces through the lens of physical chemistry, a view which has been largely absent from the discussion of catch bonds in immunology. We also aim to bring elements of physical chemistry and structural biology into predictions of immunogenicity, tackling this by considering the biophysics of protein-protein molecular recognition. Lastly, we aim to continue our work on dynamic allostery, studying how protein dynamics contribute to immune recognition and the still poorly-understood mechanism of T cell triggering. Our work remains highly collaborative and interdisciplinary, allowing it to impact multiple fields in molecular and cellular immunology and protein biophysics.