CDS&E: Simulation- and Data-driven Peptide Antibody Design Targeting RBD and non-RBD Epitopes of SARS-CoV-2 Spike Protein

CDS

• 批准号: 2152853
• 负责人: Baofu Qiao
• 金额: $ 54.94万
• 依托单位: Northwestern University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2152853&HistoricalAwards=false
• 关键词: CDS& Simulation; Data; driven; Peptide

Drugs interact with proteins to disrupt bacterial and viral infections. Effective drugs are usually discovered rather than designed. Antibodies are protein complexes generated by the immune system to bind to and inactivate viruses. Peptides are short strings of amino acids that are being designed to mimic the protein binding activity of antibodies. Many aspects of protein-protein and protein-peptide interactions are not clearly understood. This project will apply an artificial intelligence approach to understand those interactions. The SARS-CoV-2 spike protein will be the model system for study. The resulting model for therapeutic peptide design will be provided to the research community on a variety of software platforms. The project will also support outreach to K-12 students regarding the SARS-CoV-2 virus and viral infections. The overall objective is to develop a hybrid machine learning-simulation (MLSim) platform that allows us to better understand the molecular interaction between peptide drugs and viral proteins. The model viral protein system will be the SARS-CoV-2 spike proteins at both the receptor-binding domain (RBD) and the non-RBD. Transfer learning techniques for existing data models for protein-peptide interactions will be implemented. Online learning techniques will allow for the timely update of the predictive models with newly available data. The multiscale simulation component aids the machine learning part by supplying high-fidelity input data and cross-validating the predictions These efforts should result in molecular-level insight into viral protein-antibody interactions. There are two key outcomes anticipated from this project. First, a simulation- and data-enabled platform that integrates a high-throughput, customizable machine learning pipeline for fast screening and filtering peptide candidates, with high-fidelity all-atom explicit-solvent molecular dynamics simulation and free energy calculations. The second is fundamental insight into viral protein-peptide interactions and how those influence the design of neutralizing peptides.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

药物与蛋白质相互作用，破坏细菌和病毒感染。通常发现有效的药物而不是设计。抗体是免疫系统产生的蛋白质复合物，以结合和灭活病毒。肽是氨基酸的短串，这些氨基酸是为模拟抗体的蛋白质结合活性而设计的。蛋白质 - 蛋白质和蛋白质肽相互作用的许多方面尚未清楚地了解。该项目将采用人工智能方法来了解这些相互作用。 SARS-COV-2尖峰蛋白将成为研究模型系统。最终的治疗肽设计模型将通过各种软件平台提供给研究社区。该项目还将支持与K-12学生有关SARS-COV-2病毒和病毒感染的宣传。总体目标是开发混合机器学习模拟（MLSIM）平台，该平台使我们能够更好地了解肽药物和病毒蛋白之间的分子相互作用。模型病毒蛋白系统将是受体结合结构域（RBD）和非RBD的SARS-COV-2峰值蛋白。将实施针对蛋白质肽相互作用的现有数据模型的转移学习技术。在线学习技术将允许使用新可用数据及时更新预测模型。多尺度模拟组件通过提供高保真输入数据并交叉验证这些努力来帮助机器学习部分，这些努力应导致分子水平对病毒蛋白抗体相互作用的见解。该项目预期有两个关键结果。首先，一个模拟和数据支持平台，集成了用于快速筛选和过滤肽候选的高通量，可自定义的机器学习管道，具有高保真性的全原子性明显 - 溶剂分子动力学模拟和自由能计算。第二个是对病毒蛋白肽相互作用的基本洞察力，以及它们如何影响中和肽的设计。该奖项反映了NSF的法定任务，并且使用基金会的知识分子和更广泛的影响评估标准，认为值得通过评估来获得支持。