GPU-based computing for structural biophysics in immune recognition

基于 GPU 的免疫识别结构生物物理学计算

基本信息

批准号：
10796479
负责人：
Brian M Baker
金额：
$ 23.04万
依托单位：
UNIVERSITY OF NOTRE DAME
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2026-04-30
项目状态：
未结题

项目摘要

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.

抽象的我们的 NIGMS 资助的研究强调结构生物学、分子生物物理学和从广义上讲，我们的目标是将控制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、结构学等多种方法生物学、计算生物化学和分子免疫学。免疫学，我们在这个界面中的工作对于解决生物分子的基本规则具有指导意义识别和其他蛋白质行为，以及复杂系统的建模和设计。更新，我们建议继续这一跨学科重点，我们的研究强调 T 细胞受体 (TCR) 和它们的配体、短肽结合并由主要组织相容性复合体蛋白（肽/MHC TCR 识别肽/MHC 复合物是细胞免疫的基石，正如它定义的那样由于两者的高度多样性，它们具有特异性并启动导致 T 细胞免疫反应的信号传导。受体和配体，以及这些分子参与的无数过程，TCRs- 肽/MHC 相互作用被认为是生物学中最复杂的相互作用之一。面对这种异常复杂的情况，学习如何预测和操纵 TCR 识别特性以及了解 T 细胞信号传导过程的生物物理学仍然是我们研究的核心。我们的动力不仅在于获得进一步的机械洞察力的愿望，而且还在于新知识的增长基因工程 T 细胞和肽疫苗等治疗方法已经存在。免疫疗法取得了成功，但也出现了严重的并发症和令人困惑的结果。人们普遍认为，需要更好地了解免疫识别的基本原理我们未来五年的目标包括提高我们对此类疗法的理解。 TCR 交叉反应性和特异性的机制，最终目标是利用结构信息和识别交叉反应配体的建模需要我们能力的相应提高。对次优（或者我们称之为“草率”）蛋白质-蛋白质界面进行建模和评分，这是我们还计划评估 TCR 肽/MHC 界面中神秘的“捕获键”机制。从物理化学的角度来看，这种观点在捕获键的讨论中基本上没有出现我们还致力于将物理化学和结构生物学的元素引入免疫学的预测中。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。旨在继续我们在动态变构方面的工作，研究蛋白质动力学如何促进免疫识别我们对 T 细胞触发机制仍然知之甚少，但我们的工作仍然是高度协作和的。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。

项目成果

期刊论文数量（22）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

An Engineered Switch in T Cell Receptor Specificity Leads to an Unusual but Functional Binding Geometry.

T 细胞受体特异性的工程转换产生了不寻常但功能性的结合几何结构。

DOI：
发表时间：
2016-07-06
期刊：
影响因子：
0
作者：
Harris, Daniel T;Singh, Nishant K;Cai, Qi;Smith, Sheena N;Vander Kooi, Craig;Procko, Erik;Kranz, David M;Baker, Brian M
通讯作者：
Baker, Brian M

Modeling Sequence-Dependent Peptide Fluctuations in Immunologic Recognition.

免疫识别中序列依赖性肽波动的建模。

DOI：
发表时间：
2017-08-28
期刊：
影响因子：
0
作者：
Ayres, Cory M;Riley, Timothy P;Corcelli, Steven A;Baker, Brian M
通讯作者：
Baker, Brian M

Synthesis and Biological Evaluation of Hapten-Clicked Analogues of The Antigenic Peptide Melan-A/MART-126(27L)-35.

抗原肽 Melan-A/MART-126(27L)-35 的半抗原点击类似物的合成和生物学评价。

DOI：
发表时间：
2020-05-06
期刊：
影响因子：
3.4
作者：
Tarbe, Marion;Miles, John J;Edwards, Emily S J;Miles, Kim M;Sewell, Andrew K;Baker, Brian M;Quideau, Stéphane
通讯作者：
Quideau, Stéphane

Tumor rejection properties of gp100209-specific T cells correlate with T cell receptor binding affinity towards the wild type rather than anchor-modified antigen.

gp100209 特异性 T 细胞的肿瘤排斥特性与 T 细胞受体对野生型而非锚定修饰抗原的结合亲和力相关。