Molecular modeling and machine learning for protein structures and interactions

项目概要/摘要 结构生物学为观察生命系统提供了一个强大的透镜。随着算法的进步 和计算，分子模拟已经开始补充传统的实验方法作为工具， 为了发现。与此同时，数据密集型机器学习方法正变得越来越多， 在生物学中很重要，高通量实验的快速发展推动了这一点。我实验室的研究 应用结构生物学、分子模拟和机器学习技术设计新蛋白质 结构和预测蛋白质相互作用。我们设计新的蛋白质结构，以便更好地了解 蛋白质折叠的原理，并为一系列生物医学领域创造高度稳定和坚固的分子支架。 应用包括结合或信号传导结构域的多价展示，结合或催化位点的宿主， 并用作组装更高阶复合物的构件。我们预测蛋白质相互作用， 更好地理解大分子识别的原理，并深入了解 适应性免疫系统在感染性和自身免疫性疾病的背景下区分自我和非自我， 疾病和癌症。我们在项目期间的研究将朝着两个广泛的目标：重新 串联重复序列蛋白的设计和功能化，以及T细胞对肽-MHC识别的预测 受体（TCR）。建议的蛋白质设计工作建立在我们最近的进展设计环形串联 具有一系列重复数和直径的重复蛋白，并将这些设计作为多价 展示结合和信号传导结构域的支架。我们的TCR研究利用我们的工具， 最近已经发展到在结构和生物信息学上对T细胞受体及其 肽：MHC特异性。展望未来，我乐观地认为，通过结合原子详细的分子 模拟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， 构建和预测算法，对人类健康有重大的积极影响。

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.