Excellence in Research: Deep Learning based approaches for protein post-translational modification site prediction

真核细胞的复杂性不能仅仅用基因和蛋白质来解释，而是用它们复杂的调控来解释，这些调控涉及基于多种机制的相互作用。这种调控的一个重要方面是在mRNA翻译成蛋白质后进行的，因此细胞蛋白质经过修饰（翻译后修饰，PTMs）。在研究的所有生命形式中，这些修饰既影响蛋白质的结构，也影响它们的功能，包括它们在调节机制中的参与。确定这些PTM位点发生的位置对于正确阐明结构-功能关系至关重要。虽然湿实验室方法可以测试单个蛋白质修饰和功能，但计算方法是表征PTM位点的一种有前途的高通量替代方法；因此，开发准确可靠的PTM场址预测方法已成为一个重要的研究领域。该项目与nca&t的使命和目标非常吻合，正如nca&t的卓越2020所表明的那样：“在致力于更密集的研究密集型环境的同时，对教育做出坚定的承诺”。这项卓越研究（EiR）奖将使项目研究人员能够开发和建立一个独立的、高质量的研究项目，这将影响ncaa &amp；T少数民族学生的研究经验和教育。该项目旨在开发准确的基于深度学习（DL）的预测因子，用于三个重要的翻译后蛋白质修饰事件，即磷酸化，甲基化位点和SUMOylation。该项目旨在首先开发一种准确的磷酸化位点预测DL方法（研究最广泛的ptm之一），以解决采用该方法的一系列关键问题，包括所需的训练数据量、所需的架构复杂性等因素；一旦因子被定义并在磷酸化数据上进行训练，该方法将用于预测针对赖氨酸残基的其他两种类型的PTMs：甲基化和SUMOylation。该项目将提供与生物信息学应用中特定的深度学习架构使用相关的三个重要问题的见解，包括：i)所需的训练示例数量，ii)架构的复杂性与性能，以及iii)手工制作特征与简单特征的性能。此外，该项目旨在探索与使用简单特征与更复杂特征相关的问题，这些特征与生物观察相结合，以及创建计算实验所需的负数据集的最佳实践。该项目将提供一种新颖且广泛适用的基于dl的方法来预测ptm，产生更准确和完整的注释，其他研究人员可以使用这些注释来促进相关的生物学研究。将创造新的教育和外展机会，以加强学生的教育服务和技能发展，特别是在DL方法和应用方面；北卡罗来纳农工州立大学（North Carolina a&t State University）是美国最大的HBCU，其招生工作将侧重于为女性和少数族裔学生创造机会。此外，该项目将为学生建立一个国际研究体验计划，参观日本的研究实验室。本项目还将支持开展“SciPhD训练营”，为ncaa &amp；T和邻近hbcu的学生提供职业生涯准备。已开发的资源将通过http://bcb.ncat.edu.This向社会开放，该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，认为值得支持。

The complexity of eukaryotic cells cannot be explained by genes and proteins alone but, rather, by their complex regulation that involves interactions based on a number of mechanisms. One important aspect of this regulation is performed after translation of mRNA to protein, whereby cellular proteins undergo modification (post-translational modifications, PTMs). In all forms of life studied, these modifications affect both the structure of proteins and their functions, including their participation in regulatory mechanisms. Identifying where these PTM sites occur is essential to correctly elucidating structure-function relationships. While wet-lab methods can test individual protein modification and function, computational methods are a promising high-throughput alternative by which to characterize PTM sites; thus, development of accurate and reliable PTM site prediction methods has become an important area of research. The project fits well with the mission and goals of the institution, as indicated in NCA&T's Preeminence 2020: "to make a strong commitment to education while working towards a much more-intensive research-intensive environment". This Excellence in Research (EiR) award will enable the project researchers to develop and establish an independent, high-quality research program that will impact the research experience and education of minority students at NCA&T.This project aims to develop accurate Deep Learning (DL)-based predictors for the sites of three important post-translational protein modification events viz. phosphorylation, methylation sites and SUMOylation. This project aims to develop first an accurate DL approach for phosphorylation site prediction (one of the most widely studied PTMs) to tackle a host of key issues for adopting this method, including such factors as the required amount of training data, required complexity of the architecture among others; once the factors have been defined and trained on the phosphorylation data, the approach will be used to predict two other types of PTMs targeting lysine residues: methylation and SUMOylation. The project will provide insight into three important questions relevant to the use of DL architectures specific to applications in bioinformatics including: i) required number of training examples, ii) complexity of architecture vs. the performance, and iii) performance of hand-crafted features vs. simple features. In addition, the project aims to explore issues related to the use of simple features vs. more complex features that integrate biological observations, and best practices for the creation of negative datasets needed in computational experiments. The project will provide a novel and broadly applicable DL-based approach to predicting PTMs, producing more accurate and complete annotation that other researchers can then use to facilitate related biological studies. New education and outreach opportunities will be created for enhancing educational offerings and skills development in students, particularly in DL methods and applications; student recruitment will focus on creating opportunities for women and minority students at North Carolina A&T State University, the nation's largest HBCU. In addition, the project will establish an international research experience program for students, to visit research labs in Japan. This project will also provide support to conduct the "SciPhD Bootcamp" for professional career preparation for students from NCA&T and neighboring HBCUs. The developed resources will be accessible to the community at http://bcb.ncat.edu.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.