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

生物纳米机器是在活的有机体中执行所有基本生物过程的组件。电子冷冻显微镜是确定生物纳米机器分子结构的最合适的结构工具，生物纳米机器通常由总质量大于50万道尔顿的多个蛋白质亚单位和/或核酸组成。目标是开发信息发现和集成方法，以推导出纳米机器的原子模型。这样的模型将从3维(3-D)低温EM质量密度函数(即体积密度图)与蛋白质折叠和信息学数据的物理结合而得到。这个项目是由五名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EM体密度中提取结构信息，并将这些信息整合到经典的蛋白质结构建模范式中，如比较建模和从头建模，以了解生物纳米机械，这一研究的智能优势得到了突出的体现。三个研究目标包括信息发现、信息集成和算法验证。这项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，该小组将向学术界免费分发所产生的工具，并将在项目接近尾声时主办一次讲习班。为了提高研究的影响力，调查人员将把研究与每个成员机构的教育结合起来，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一门关于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.