Molecular modeling and machine learning for protein structures and interactions

蛋白质结构和相互作用的分子建模和机器学习

• 批准号: 10191763
• 负责人: Philip Bradley
• 金额: $ 13.13万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10191763
• 关键词: Adaptive Immune System; Algorithms; Antigens; Autoimmune Diseases; Binding; Binding Sites; Bioinformatics; Biology; Caliber; Catalytic Domain; Cell Therapy; Communicable Diseases; Complement; Complex; Computational algorithm; Data; Diagnostic; Goals; Health; Human; Immune system; Laboratories; Machine Learning; Malignant Neoplasms; Molecular; Molecular Machines; Organism; Peptide/MHC Complex; Process; Protein Engineering; Proteins; Research; Signal Transduction; Specificity; Structural Models; T-Cell Receptor; T-cell receptor repertoire; Tandem Repeat Sequences; Techniques; Time; Work; design; insight; lens; molecular modeling; prediction algorithm; protein folding; protein structure; rapid growth; scaffold; simulation; structural biology; tool

PROJECT SUMMARY / ABSTRACT Structural biology provides a powerful lens through which to view living systems. With advances in algorithms and computing, molecular simulations have begun to complement traditional experimental approaches as tools for discovery. At the same time, data-intensive machine learning approaches are becoming increasingly important in biology, fueled by the rapid growth in high-throughput experimentation. Research in my laboratory applies techniques from structural biology, molecular simulation, and machine learning to design new protein structures and predict protein interactions. We design new protein structures in order to better understand the principles of protein folding and to create highly stable and robust molecular scaffolds for a range of biomedical applications including multivalent display of binding or signaling domains, hosting of binding or catalytic sites, and use as building blocks to assemble higher-order complexes. We predict protein interactions in order to better understand the principles of macromolecular recognition and to gain insight into the process by which the adaptive immune system discriminates self from non-self in the context of infectious and autoimmune diseases and cancer. Our research during the project period will be directed toward two broad goals: de novo design and functionalization of tandem repeat proteins, and prediction of peptide-MHC recognition by T cell receptors (TCRs). The proposed protein design work builds on our recent progress designing circular tandem repeat proteins with a range of repeat numbers and diameters and applying these designs as multivalent display scaffolds for the presentation of binding and signalling domains. Our TCR studies leverage the tools we have recently developed to model—structurally and bioinformatically—repertoires of T cell receptors and their peptide:MHC specificity. Looking ahead, I am optimistic that by combining atomically-detailed molecular simulations and data-intensive machine learning techniques we will be able to generate designed protein constructs and predictive algorithms that have a significant positive impact on human health.

项目摘要 /摘要 结构生物学提供了一个强大的镜头，可以通过该镜头来查看生活系统。随着算法的进步 和计算，分子模拟已开始将传统的实验方法作为工具补充 用于发现。同时，数据密集型机器学习方法变得越来越多 在生物学中很重要，这是由于高通量实验的快速增长所推动的。我的实验室研究 应用结构生物学，分子模拟和机器学习的技术来设计新蛋白 结构并预测蛋白质相互作用。我们设计了新的蛋白质结构，以便更好地了解 蛋白质折叠的原理，并为一系列生物医学创建高度稳定和稳健的分子支架 应用程序，包括绑定或信号域的多价显示，结合或催化位点的托管， 并用作组合块来组装高阶复合物。我们预测蛋白质相互作用以便 更好地了解大分子识别的原则，并深入了解该过程 自适应免疫系统在传染性和自身免疫性的背景下将自我歧视 疾病和癌症。我们在项目期间的研究将针对两个广泛的目标：从头开始 串联重复蛋白的设计和功能化，以及T细胞对肽-MHC识别的预测 接收器（TCR）。拟议的蛋白质设计工作以我们最近的进度设计为基础 重复具有一系列重复数和直径的蛋白质，并将这些设计应用于多价 显示脚手架，用于呈现结合和信号域。我们的TCR研究利用了我们的工具 最近开发了建筑和生物信息建模的T细胞受体及其的替代 肽：MHC特异性。展望未来，我很乐观，通过结合原子详细的分子 仿真和数据密集型机器学习技术我们将能够生成设计的蛋白质 对人类健康产生重大积极影响的构造和预测算法。