CAREER: A Computational Framework for Mapping Ligand Migration Channel Networks and Predicting Molecular Control Mechanisms

职业：用于绘制配体迁移通道网络和预测分子控制机制的计算框架-项目摘要蛋白质是生物体的基本元素。它们是不可思议的微观生物机器，以稳定、可预测的方式运作。它们与DNA等其他元素一起构成了构成生命复杂性的基础。对这些生物机器如何工作的探索激发了强烈的科学好奇心和想象力。由于大多数函数是动态执行的，很难从实验中直接观察到，因此计算方法具有重要的、不可替代的作用。本提案的目的是绘制蛋白质内部的配体迁移通道网络，并确定这些通道动态调节的分子控制机制。为了克服现有方法面临的局限性，该项目将开发和采用一种新颖、高效的计算框架，该框架的灵感之一来自机器人的路径规划，作为配体？动态蛋白质中的S迁移与移动机器人非常相似。S在动态环境中的导航。提出的方法将有效的几何映射与蛋白质的动态探索相结合，从而克服了计算障碍。S结构灵活性。通过将给定蛋白质的结构集合（可能由现有的实验结构和/或分子动力学模拟生成的构象组成）作为输入，该方法对蛋白质进行空间映射。在集合中每个构象的S内空间。空间映射揭示了蛋白质内部空腔和通道的部分连通性。然后将所有部分图合并形成一个超级图，该超级图表示配体在空间和动态上可访问的完整迁移通道网络。该方法将用于绘制蛋白质家族中的配体迁移通道网络，并研究整个家族中配体通道网络的异同，这是一种新颖的方法。此外，由于通道网络是针对整体中每个单独的构象绘制的，因此将收集和分析构象变化与通道大小变化之间的直接相关数据，以确定调节这些通道的关键构象变化。然后将确定导致关键构象变化的关键残基。作为一名大学教授，PI观察到本科生课堂普遍缺乏动力和灵感，研究生需要更多的创造性思维的灵感训练。为了满足这些迫切的需求，本提案的教育目标是：i)在本科课堂中注入科学的好奇心和动力，ii)培养有动力的本科生和研究生成为创造性的思想家，以及iii)将学习和发现的兴奋传播给社区，初中生和高中生。首席研究员相信，他的研究的跨学科性质，应提供宝贵的资源，以激发学生的科学好奇心和激发跨学科的创造性思维。智力优势：该项目将开发一种新的计算框架，用于绘制配体迁移通道网络。在该项目完成后，预计将对调节配体迁移通道网络的控制机制有一个清晰的认识。关键控制残基或分子开关将被识别。蛋白质运动和动力学的精确作用将被描述。这种对功能机制的理解可以用来解释现有的实验结果或做出新的预测，以指导未来的实验。更广泛的影响：建议的研究活动将与教育活动紧密结合。π吗?美国的跨学科研究将用于培养学生的科学好奇心和跨学科的创造性思维，特别是对女性、缺乏服务的少数民族和残疾人。该项目将为本科生和研究生创造充分的机会参与研究，并培养他们成为创造性的思想家。研究成果将通过期刊出版物和会议报告广泛传播。该项目开发的计算框架将为科学界提供一个宝贵的工具，可以用于研究许多其他生物分子的分子控制机制。

CAREER: A computational framework for mapping ligand migration channel networks and predicting molecular control mechanisms - Project SummaryProteins are fundamental elements of living organisms. They are marvelous microscopic bio-machines that function in a steady, predictable manner. Together with other elements such as DNA, they make up the basics that underlie the complexity of life. The quest to know how these bio-machines work has inspired intense scientific curiosity and imagination. Since most functions are carried out dynamically and are difficult to observe directly from experiments, computational methods have an important, irreplaceable role to play.The objective of this proposal is to map out the ligand migration channel networks inside proteins and determine the molecular control mechanisms by which these channels are regulated dynamically. To overcome the limitations that existing methods face, the project will develop and employ a novel, efficient computational framework that draws one of its inspirations from path planning in robotics, as a ligand?s migration in a dynamic protein resembles closely a mobile robot?s navigation in a dynamic environment. The proposed approach will overcome the computational barrier by integrating efficient geometric mappings with the dynamic exploration of a protein?s structure flexibility. By taking as input the structure ensemble of a given protein, which may be composed of existing experimental structures and/or conformations generated from molecular dynamics simulations, the proposed method carries out a spatial mapping of the protein?s inner space at each conformation in the ensemble. The spatial mapping reveals the partial connectivity of the cavities and channels inside the protein. All partial maps are then merged to form a super-graph that represents the complete migration channel network that is accessible to the ligand, spatially and dynamically. The method will be applied to map out the ligand migration channel networks in a family of proteins and to study the similarities and differences in the ligand channel networks across the family, which is novel. Moreover, since the channel network is mapped for each individual conformation in the ensemble, direct correlation data between conformation changes and variations in channel sizes will be collected and analyzed to identify the key conformation changes that regulate these channels. Key residues that are responsible for the key conformation changes will then be identified. As a university professor, the PI has observed the prevalent lack of motivation and inspiration in undergraduate classrooms and the need for more inspired training in creative thinking among graduate students. To address these pressing needs, the education objectives of this proposal are: i) to infuse scientific curiosity and motivation into the undergraduate classrooms, ii) to train motivated undergraduate and graduate students to become creative thinkers, and iii) to spread the excitement of learning and discovery to the community, to junior high and high school students. The PI believes that the inter-disciplinary nature of his research should provide invaluable resources to engender scientific curiosity and to inspire cross-disciplinary creative thinking among the students. Intellectual merits: the project will develop a novel computational framework for mapping ligand migration channel networks. Upon completion of this project, it is expected that a clear understanding of the control mechanism by which ligand migration channel networks are regulated will have been developed. Key control residues, or molecular switches, will be identified. The precise roles of protein motions and dynamics will be delineated. Such an understanding of functional mechanisms can be used to interpret the existing experimental results or make new predictions that can guide future experiments.Broader impacts: the proposed research activities will be closely integrated with education activities. The PI?s interdisciplinary research will be used to cultivate scientific curiosity and cross-disciplinary creative thinking among students, especially for women, underserved minorities and the disabled. The project will create ample opportunities for undergraduate and graduate students to participate in research and to be trained to become creative thinkers. The research results will be broadly disseminated through journal publications and conference presentations. The computational framework developed in this project will provide the scientific community with an invaluable tool that can be adapted to study the molecular control mechanisms of many other bio-molecules.