III-CXT:Collaborative Research: Integrated Modeling of Biological Nanomachines

生物纳米机器是在生物体中执行所有基本生物过程的组件。电子冷冻显微镜（cryoEM）是确定生物纳米机器分子结构的最合适的结构工具，这些机器通常由多个蛋白质亚基和/或总质量大于50万道尔顿的核酸组成。目标是开发信息发现和集成方法，用于派生纳米机器的原子模型。这些模型将由三维（3-D）低温电磁质量密度函数（即体积密度图）与蛋白质折叠物理和信息学数据相结合得出。这个项目是由五位研究人员在计算机图形学、计算生物物理学、结构信息学和低温电子显微镜方面的专业知识整合而成的。从低分辨率、复杂的低温体积密度中提取结构信息的计算方法，并将这些信息整合到经典的蛋白质结构建模范式中，如比较建模和从头算建模，以理解生物纳米机器，突出了本研究的智力价值。三个研究目标包括信息发现、信息集成和算法验证。拟议的研究将对三个不同的学科产生重大影响：计算机科学，分子建模和低温电子显微镜。此外，该团队将免费向学术界传播他们的工具，并将在项目结束时举办研讨会。为了提高研究的影响力，研究人员将把每个成员机构的研究与教育结合起来，着眼于多样性。特别是，这些研究人员将为五个参与机构的研究生和大四本科生开发生物纳米机器建模的虚拟教学课程。

Biological nanomachines are the assemblies that carry out all the basic biological processes in a living organism. Electron cryo-microscopy (cryoEM) is the most appropriate structural tool to determine molecular structures of biological nanomachines that generally consist of multiple protein subunits and/or nucleic acids with a total mass greater than 0.5 million Daltons. The goal is to develop information discovery and integration methodologies for deriving atomic models of nanomachines. Such models will be derived from 3-dimensional (3-D) cryoEM mass density function (i.e. a volumetric density map) in conjunction with physics of protein folding and informatics data. This project is made possible by an integration of the expertise of five investigators in computer graphics, computational biophysics, structural informatics and cryoEM. The intellectual merit of this research is highlighted by the computational approaches of extracting structural information from low-resolution, complex cryoEM volume densities and integrating this information into classical protein structure modeling paradigms, such as comparative modeling and ab initio modeling, for understanding biological nanomachines. The three research goals involve information discovery, information integration and validation of the proposed algorithms. The proposed research will have significant impacts in three disparate disciplines: computer science, molecular modeling, and cryoEM. Furthermore, the team will disseminate their resulting tools freely to the academic community and will host a workshop towards the end of the project. To enhance the impact of their research, the investigators will integrate research with education at each member institution with an eye towards diversity. In particular, these investigators will develop a virtual didactic course in modeling of biological nanomachines for graduate and senior undergraduate students at the five participating institutions.