Biophysical Characterization of Novel Protein Dynamics in the Adaptive Immune System

Biophysics is the study of the form and function of life’s machines. It combines the fields of biology, biochemistry, physics, and mathematics to study microscopic phenomena. The components of the immune system that confer a response are full of complexity. However, this complexity is simplified if we recognize that their processes evolved harmonically. By learning the fundamental biophysics of aspects of the adaptive immune system, we can establish the basis for the complexities of the immune response. We study these fundamentals through a cornerstone of adaptive immunity: the protein-protein interaction between the specialized receptors of T cells of the immune system and the complex of a peptide presented by a major histocompatibility complex (MHC) protein.

T cell receptors (TCRs) bind the composite interface of peptide/MHC (pMHC) proteins as a necessary first step to the T cell immune response. Many studies of TCR-pMHC interactions have provided considerable insight into the determinants of TCR recognition, including TCR preferences for peptides and the ‘rules’ of TCR binding and subsequent immune responses. These central ideas have been integrated into various approaches to predict TCR specificity and peptide immunogenicity. However, there exist many exceptions to these rules, such as peptide conformational adaptability and alternative TCR engagement.

Here, we use a combination of experimental and computational biophysics techniques to determine the mechanism and minimal determinants of a peptide conformational change and the superantigenic capabilities of the SARS-CoV-2 spike protein.

As new and further advanced techniques in biophysical analysis arise, especially with the introduction of artificial intelligence in computational methodology, it is imperative that we approach these studies with insight and a realistic understanding of the scope of our research. If we can define the biophysics and inherent dynamics of the proteins that induce an immunological response, we can predict and control the functions of these molecules, with broad implications for immunotherapy and the field of immunology.

生物物理学（Biophysics）是研究生命运作机器的形态与功能的学科，它融合生物学、生物化学、物理学与数学等多领域知识，用以探究微观生命现象。介导免疫应答的免疫系统组分蕴含极高复杂性，但倘若我们认识到其进程以协同协调的方式演化，此类复杂性便可得以简化。通过解析适应性免疫系统相关组分的基础生物物理学特性，我们可为理解免疫应答的复杂机制奠定根基。我们以适应性免疫的核心基石为载体开展此类基础研究：即免疫系统T细胞的特异性受体，与主要组织相容性复合体（major histocompatibility complex, MHC）蛋白呈递的肽段复合物之间的蛋白质-蛋白质相互作用。

T细胞受体（T cell receptors, TCRs）与肽段-MHC复合物（peptide/MHC, pMHC）的复合结合界面相结合，这是T细胞免疫应答启动的必要首要步骤。诸多针对TCR-pMHC相互作用的研究，已为解析T细胞识别的决定性因素提供了大量洞见，其中包括TCR对肽段的偏好性，以及TCR结合与后续免疫应答的相关"规则"。此类核心认知已被整合至多种用于预测TCR特异性与肽段免疫原性的方法之中，但此类规则存在诸多例外，例如肽段的构象适应性，以及TCR的其他结合模式。

本研究结合实验生物物理学与计算生物物理学技术，旨在解析肽段构象变化的机制与最小决定性因素，以及严重急性呼吸综合征冠状病毒2（SARS-CoV-2）刺突蛋白的超抗原活性。

随着生物物理分析技术的不断革新与精进，尤其是人工智能（artificial intelligence, AI）应用于计算研究方法后，我们必须以敏锐的洞察力与对研究边界的清醒认知来开展此类研究。倘若我们能够阐明介导免疫应答的蛋白质的生物物理学特性与固有动力学特征，便可预测并调控此类分子的功能，这将为免疫治疗与免疫学领域带来广泛的应用前景。