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-项目概述蛋白质是生物体的基本元素。它们是奇妙的微观生物机器，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。由于大多数功能是动态进行的，很难直接从实验中观察到，计算方法有一个重要的，不可替代的作用play. This建议的目的是绘制出的配体迁移通道网络内的蛋白质和确定的分子控制机制，这些通道的动态调节。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的，高效的计算框架，从机器人路径规划中汲取灵感，作为配体？在动态蛋白质中的迁移非常类似于一个移动的机器人？在动态环境中的导航。所提出的方法将克服计算障碍，通过整合高效的几何映射与蛋白质的动态探索？的结构灵活性。作为输入的结构合奏的一个给定的蛋白质，这可能是由现有的实验结构和/或分子动力学模拟产生的构象，所提出的方法进行了空间映射的蛋白质？的内部空间在每个构象在合奏。空间映射揭示了蛋白质内部空腔和通道的部分连通性。然后合并所有部分图以形成代表配体在空间上和动态地可访问的完整迁移通道网络的超级图。该方法将应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相似性和差异性，这是新颖的。此外，由于通道网络被映射为系综中的每个个体构象，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，以识别调节这些通道的关键构象变化。然后将鉴定负责关键构象变化的关键残基。 作为一名大学教授，PI观察到本科生课堂上普遍缺乏动机和灵感，研究生需要更多的创造性思维培训。为了满足这些迫切的需求，本提案的教育目标是：i）将科学好奇心和动机注入本科生课堂，ii）培养有动力的本科生和研究生成为创造性思维者，以及iii）将学习和发现的兴奋传播到社区，初中和高中学生。PI认为，他的研究的跨学科性质应该提供宝贵的资源，以产生科学的好奇心，并激发学生的跨学科创造性思维。智力优点：该项目将开发一种新型计算框架来绘制配体迁移通道网络。完成本项目后，预计将开发出对配体迁移通道网络调节的控制机制的清晰理解。关键控制残基，或分子开关，将被确定。蛋白质运动和动力学的确切作用将被描绘出来。这样的功能机制的理解可以用来解释现有的实验结果或作出新的预测，可以指导未来的实验。更广泛的影响：拟议的研究活动将与教育活动紧密结合。私家侦探？的跨学科研究将被用来培养学生的科学好奇心和跨学科的创造性思维，特别是对妇女，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，并接受培训，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.