Integration of biophysics and deep learning to understand species-specificity of fertilization and the rapid evolution of protein disorder

项目摘要 蛋白质通常折叠成三维形状，并作为细胞机器运行，具有明确的 反应机制--因此有一句常见的生物化学表述：“结构就是功能。”然而，这条规则 只适用于人类基因组进化最慢的部分。进化得更快的蛋白质是 通常不那么有序，既实现了它们的加速进化，又扩大了生物化学的图景 自然选择可能会起作用。目前，很少有工具和概念框架来理解 快速进化动态蛋白质的序列-功能关系。穿过生命之树，繁衍生息 蛋白质以非同寻常的速度进化--通常比免疫基因更快--威尔本实验室研究了 动物物种特异性受精的生物物理学和分子进化。生物多样性的持续协同进化 相互作用的精子和卵子蛋白被选为生化特性，如内在障碍，虚弱 结合亲和力等，使他们的研究复杂化。高场核磁共振波谱在结构中是独一无二的 方法研究这种异质蛋白质系统，我开创了核磁共振研究的先河。 受精蛋白是受精研究的经典模型(海洋鲍鱼)。在未来5年，我们将 询问配子识别蛋白的序列与功能的关系，这些蛋白质对物种特异性很重要 通过将高通量突变筛选与有针对性的生物物理分析相结合进行受精，以更好地 了解分子动力学与蛋白质进化性和相互作用动力学的复杂相互作用。核磁共振 方法将扩展到哺乳动物受精蛋白的研究。为了方便我们自己的工作和 增强其他研究人员的能力，基于深度学习的进化基因组学、质谱仪等分析工具 蛋白质组学和核磁共振动力学将得到发展。拟议的研究将提供一种进化性的 框架，以更好地理解由人类基因组编码的蛋白质生物化学的广度，以及 包括为本科生、研究生和博士后提供的各种培训机会

Project Summary Proteins often fold into three-dimensional shapes and operate as cellular machines with well-defined reaction mechanics – hence the common biochemical expression “structure is function.” However, this rule only applies to the slowest evolving portions of the human genome. Proteins that evolve more rapidly are typically less ordered, both enabling their accelerated evolution and expanding the biochemical landscape on which natural selection may act. Currently there exist few tools and conceptual frameworks to understand the sequence-function relationship of quickly evolving dynamical proteins. Across the tree of life, reproductive proteins evolve at extraordinary rates – typically faster than immune genes – and the Wilburn lab studies the biophysics and molecular evolution of species-specific fertilization in animals. The continuous coevolution of interacting sperm and egg proteins has selected for biochemical properties such as intrinsic disorder, weak binding affinities, etc. that complicate their study. High-field NMR spectroscopy is unique among structural methods in its ability to study such heterogenous protein systems, and I have pioneered NMR studies of fertilization proteins in a classic model of fertilization research (marine abalone). Over the next 5 years, we will interrogate the sequence-to-function relationships of gamete recognition proteins important for species-specific fertilization by pairing high throughput mutagenesis screens with targeted biophysical analyses to better understand the complex interplay of molecular dynamics with protein evolvability and interaction kinetics. NMR methods will be expanded to the study of mammalian fertilization proteins. To facilitate our own work and empower other researchers, deep learning-based analytical tools in evolutionary genomics, mass spectrometry proteomics, and NMR dynamics will be developed. The proposed research will provide an evolutionary framework to better understand the breadth of protein biochemistry encoded by the human genome, and includes diverse training opportunities for undergraduate, graduate students, and postdocs