PROTEAN-CR: Proteomics Toolkit for Ensemble Analysis in Cancer Research

PROTEAN-CR：用于癌症研究中整体分析的蛋白质组学工具包

• 批准号: 10188196
• 负责人: Lydia E. Kavraki
• 金额: $ 40.21万
• 依托单位: RICE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10188196
• 关键词: Accounting; Address; Adopted; Algorithms; Binding; Biological; Cancer Center; Cancer Diagnostics; Cellular immunotherapy; Clinical Research; Collaborations; Communities; Complement; Complex; Computer software; Computer-Aided Design; Computers; Country; Custom; Cyclic Peptides; Data; Data Aggregation; Data Analytics; Data Science; Databases; Development; Dimensions; Disease; Docking; Drug resistance; Estrogen Receptors; Evolution; Funding; Genetic Polymorphism; Goals; Greek; HLA Antigens; Intuition; Letters; Ligand Binding; Ligands; Malignant Neoplasms; Methodology; Methods; Modeling; Molecular; Molecular Conformation; Molecular Structure; Mutation; Mythology; Nature; Occupations; Peptides; Phosphopeptides; Phosphorylated Peptide; Play; Post-Translational Protein Processing; Process; Protein Analysis; Protein Conformation; Proteins; Proteomics; Public Health; RNA Editing; Research; Research Personnel; Resources; Role; Running; Sampling; Structural Models; Structure; System; T-Lymphocyte; The Cancer Genome Atlas; Tumor Antigens; Variant; Visualization; Work; anticancer research; base; cancer immunotherapy; cancer therapy; computational pipelines; computerized tools; data acquisition; design; driver mutation; drug discovery; experience; flexibility; improved; in silico; innovation; interest; machine learning method; malignant breast neoplasm; melanoma; multi-scale modeling; novel diagnostics; novel therapeutics; peptide based vaccine; programs; prototype; receptor; scale up; screening; three dimensional structure; tool; tumor; user-friendly; vaccine development; web app

Project Summary Understanding protein–ligand molecular interactions is fundamental to understanding the role of proteins in complex diseases such as cancer. For instance, there is growing interest in predicting the binding modes of peptide-based ligands (e.g., cyclic and phosphorylated peptides) to inhibit or induce targeted degradation of high-profile cancer targets. Another promising example is the identification of tumor-associated antigens for cancer immunotherapy applications. Both examples involve very specific molecular interactions, provide opportunities for computer-aided design of better cancer treatments, and highlight the need for structural analyses in cancer research. They also require new methods that account for the flexibility and variability of the protein receptors involved in these molecular interactions. The objective of this project is to develop an integrated approach to the structural modeling and analysis of protein–ligand interactions in cancer research that will be implemented in the proteomics toolkit PROTEAN-CR. The proposed toolkit will adopt a data-science approach to the problem by introducing approaches for data acquisition and aggregation, as well as algorithmic advances for handling receptor flexibility and for modeling driver mutations, drug-resistance polymorphisms, and post-translational modifications. PROTEAN-CR will streamline running structural analyses at scale while providing meaningful data analytics. The long-term goal of our research is to fully integrate three-dimensional structural information about proteins and ligands and structural analysis into cancer research. The PIs will work with collaborators to target a wide range of users, from experimentalists with little to no programming experience, to advanced users who are comfortable scripting large-scale analyses and integrating the toolkit with their own computational pipeline. The central hypothesis is that a unified data-science-inspired approach can be used to address major challenges in structural analysis of protein–ligand interactions in cancer research at scale. The first aim will incorporate protein flexibility in docking studies for cancer research. Specific workflows will be used to generate ensembles of protein conformations (receptor flexibility) and innovative machine learning methods will be implemented aiming at a better scoring of protein–ligand complexes. The second aim will focus on including cancer variability into structural analysis. We aim to fill the gap that exists between available data on cancer variants and the structural analysis of ensembles of tumor-associated mutations and protein modifications. Finally, the third aim will focus on customization, interpretability and scalability, where user-friendly methods will be deployed to manage ensembles of protein-ligand complexes. PROTEAN-CR will be developed focusing on specific cancer-related projects, and with a broad network of collaborators, enabling the design, implementation and evolution of the tool according to the needs of the cancer research community.

项目概要 了解蛋白质-配体分子相互作用是理解蛋白质在生物体内的作用的基础。 复杂的疾病，例如癌症。例如，人们对预测结合模式越来越感兴趣 基于肽的配体（例如环状肽和磷酸化肽）可抑制或诱导 备受瞩目的癌症目标。另一个有希望的例子是识别癌症的肿瘤相关抗原 免疫治疗应用。这两个例子都涉及非常具体的分子相互作用，提供了机会 计算机辅助设计更好的癌症治疗方法，并强调癌症结构分析的必要性 研究。他们还需要新的方法来解释蛋白质受体的灵活性和可变性 参与这些分子相互作用。该项目的目标是开发一种综合方法 癌症研究中蛋白质-配体相互作用的结构建模和分析，将在 蛋白质组学工具包 PROTEAN-CR。拟议的工具包将采用数据科学方法来解决问题 通过引入数据采集和聚合方法以及处理算法的进步 受体灵活性以及驱动突变、耐药多态性和翻译后建模 修改。 PROTEAN-CR 将简化大规模结构分析的运行，同时提供有意义的数据 分析。我们研究的长期目标是充分整合三维结构信息 蛋白质和配体以及癌症研究中的结构分析。 PI 将与合作者合作以实现目标 广泛的用户，从几乎没有编程经验的实验者到具有编程经验的高级用户 能够轻松编写大规模分析脚本并将工具包与自己的计算管道集成。 中心假设是，可以使用统一的数据科学启发方法来应对重大挑战 大规模癌症研究中蛋白质-配体相互作用的结构分析。第一个目标将包括 癌症研究对接研究中的蛋白质灵活性。特定的工作流程将用于生成 将实施蛋白质构象（受体灵活性）和创新的机器学习方法，目标是 对蛋白质-配体复合物进行更好的评分。第二个目标将侧重于将癌症变异性纳入 结构分析。我们的目标是填补癌症变异的可用数据与结构性数据之间存在的差距 肿瘤相关突变和蛋白质修饰的整体分析。最后，第三个目标将集中于 定制、可解释性和可扩展性，将部署用户友好的方法来管理集成 蛋白质-配体复合物。 PROTEAN-CR 将重点开发特定的癌症相关项目，并且 拥有广泛的合作者网络，使该工具的设计、实施和发展能够根据 癌症研究界的需求。