CAREER: Sparse Spatial Reasoning for High-Throughput Protein Structure Determination

这是一个教师早期职业发展（Career）奖。该研究将开发新的方法来分析蛋白质分子的结构，解释包含显著噪声和稀疏信息内容的空间数据集。尽管有许多实验和计算方面的进步，传统的结构确定方案仍然非常困难、昂贵和耗时。因此，为了提高结构确定的吞吐量，研究人员正在追求提供更少、更快的结构信息的极简技术；例子包括突变研究，表明在哪些位置的氨基酸替换会显著影响蛋白质的功能；交联质谱法，提供蛋白质中某些位置的粗略接近信息；电子显微镜，在相对较低的分辨率下阐明蛋白质的表面/体积。这些极简实验给实验计划和数据解释的相关算法带来了更多的负担。本项目寻求新的理论、表示和算法来解决以稀疏空间数据为特征的领域中的数据解释和实验设计问题。该研究的一个重要组成部分是极简蛋白结构测定的案例研究应用。该教育计划解决了在计算机科学和生命科学之间建立桥梁的需要，以便解决这种计算与实验相结合的问题。将开发一个空间推理器，利用关键问题结构来高效和有效地计划和解释实验。它将用多层次、多维的拓扑和几何对象和约束来表示数据、模型和生物物理知识。这种表示将允许算法匹配数据和模型的特征，通过发现一致的特征集来克服噪声和稀缺性问题，针对冲突澄清目标查询，并计划额外的实验。因此，这种方法将支持建模和实验的闭环集成——实验证据将引发对模型特征的评估，甚至模型本身的优化，而模型分析将引发具体的数据解释问题，甚至新的实验。该项目的教育部分将计算机科学和生命科学的学生聚集在一起，训练他们进行跨学科的计算生物学研究。与普渡大学计算机科学系和计算科学与工程项目共同开发的额外和修订的课程将结合先进的计算技术和生物应用。该培训将为生命科学专业的学生提供必要的算法背景，并为计算机科学专业的学生提供必要的接触和经验，以激发生物学问题。研究机会、课程项目和其他学习机会将进一步使学生参与许多具有挑战性和迷人的生物学问题，这些问题需要先进的计算技术。该奖项旨在表彰和支持有可能成为21世纪学术领袖的教师学者的早期职业发展活动。这项研究将在生物分子机制的结构和功能理解方面做出科学贡献。在为该应用程序开发、应用和扩展算法时所面临的挑战将导致对物理系统推理的核心贡献，在物理系统中，许多类似的规划、建模、预测和控制任务面临稀疏、嘈杂空间数据的类似问题。

This is a Faculty Early Career Development (CAREER) award. The research will develop new methods for analyzing the structure of protein molecules, interpreting spatial data sets containing significant noise and sparse information content. Despite many experimental and computational advances, traditional structure determination protocols remain very difficult, expensive, and time-consuming. Consequently, in order to increase the throughput of structure determination, researchers are pursuing minimalist techniques that provide much less structure information much faster; examples include mutation studies, indicating at which positions amino acid substitutions significantly affect the protein's function; cross-linking mass spectrometry, providing crude proximity information for some positions in the protein; and electron microscopy, elucidating the protein's surface/volume at relatively low resolution. These minimalist experiments then place more burden on associated algorithms for experiment planning and data interpretation.This project pursues new theory, representations, and algorithms to address data interpretation and experiment design problems in domains characterized by sparse spatial data. A significant component of the research is the case study application of minimalist protein structure determination. The education plan addresses the need to build bridges between computer science and the life sciences in order to attack problems of this combined computational-experimental kind.A spatial reasoner will be developed, leveraging key problem structure to efficiently and effectively plan and interpret experiments. It will represent data, models, and biophysical knowledge with multi-level, multi-dimensional topological and geometric objects and constraints. This representation will allow algorithms to match features of data and models, overcome problems of noise and scarcity by uncovering consistent feature sets, target clarifying queries in response to conflicts, and plan additional experiments. This approach will thus support closed-loop integration of modeling and experiment -- experimental evidence will trigger evaluation of model features and even optimization of models themselves, while model analysis will trigger specific data interpretation questions and even new experiments.The education component of this project brings together students from computer science and the life sciences to train them for interdisciplinary computational biology research. Additional and revised coursework, to be developed in conjunction with the Computer Science Department and Computational Science and Engineering program at Purdue, will combine advanced computational techniques and biological applications. The training will provide life science students with the necessary algorithmic background and computer science students with the necessary exposure to and experience with motivating biological problems. Research opportunities, course projects, and other learning opportunities will further involve students in the many challenging and fascinating biological problems requiring advanced computational techniques.This CAREER award recognizes and supports the early career-development activities of a teacher-scholar who is likely to become an academic leader of the twenty-first century. The research will lead to scientific contributions in the structural and functional understanding of biomolecular machinery. The challenges faced in developing, applying, and extending algorithms for this application will lead to core contributions in reasoning about physical systems, where many similar tasks in planning, modeling, predicting, and controlling face similar problems with sparse, noisy spatial data.