CAREER: Critical Issues for Biomolecular Simulations: Organic Solvents, Protein-Protein and Nucleotide-Protein Interactions

该职业奖支持计算生物物理学的研究和教育。研究活动将侧重于生物分子应用，并建立在PI在处理生物分子之间的长程静电相互作用以及新的多尺度发展方面所取得的方法学进展的基础上。具体的研究目标主要集中在核酸识别方面，以及发生在Ras超家族GTP酶中的蛋白质-蛋白质相互作用。关键细胞过程，如DNA复制、修复和转录、mRNA翻译、病毒RNA插入等，都涉及蛋白质和核酸之间复杂的相互作用。这些相互作用的真实的、基于物理学的特征仍然是难以捉摸的，因为它们的量级相对较小，而且它们的物理起源多种多样。这些相互作用决定了分子之间的“识别”接触，这使得位点特异性结合蛋白能够从数百万种可能性中选择正确的核酸序列。类似的复杂性和技术难度的概念也适用于蛋白质-蛋白质相互作用。作为大规模生物分子模拟研究的特定模型，PI选择了GTP酶家族，其作为参与哺乳动物细胞中信号转导级联和运动的分子开关。此外，PI还将研究用于测定蛋白质表面结合位点的选定有机溶剂的性质。在实验上，已经确定许多蛋白质在各种有机溶剂中的溶剂化结构与在水环境中的结构几乎相同。因此，有机溶剂允许实验人员通过多溶剂晶体结构（MSCS）方法探测蛋白质的结合位点。目前，对蛋白质与有机分子溶剂化的性质几乎没有理论认识，因此这是一个重要的研究机会。PI计划与NC State和当地NIH实验室的其他研究人员协商和合作开展这些调查。PI将专注于教授两门课程，展示生物分子模拟的力量和本CAREER提案中概述的应用。这些课程旨在满足当地对原子模拟方法调查课程和生物分子模拟密集“短期课程”的需求。这些课程将成为高性能超级计算中心（CHiPS）教育工作的一部分。计划从代表性不足的群体中招收学生，特别是妇女和西班牙裔学生，并参与国际合作，这些计划被纳入研究和教育活动。更广泛的影响：研究部分影响定量生物学以及理论和计算材料研究领域。教育部分支持具有计算能力的世纪劳动力，并为代表性不足的群体成员提供机会。%该职业奖支持计算生物物理学领域的综合研究和教育计划。基于最近的算法进步与并行计算的不断增长的能力相结合，现在有可能直接研究具有分子动力学模拟能力的生物分子的作用。PI的研究将主要集中在：（i）用于测定蛋白质表面性质的有机溶剂;（ii）溶液中的DNA序列依赖性结构;（iii）发生在Ras超家族GTP酶中的蛋白质-蛋白质相互作用。对这些系统的研究将是提高我们对基本生物分子过程理解的重要一步。本CAREER提案的教育目标基于研究生“多尺度”教育的概念，该教育将在一个新开发的中心的主持下进行，旨在促进高性能超级计算，即，一种教育，确保学生有一套广泛的计算模拟技能在他们的处置，而不是集中在一个狭窄的领域。为此，PI -谁是该中心的积极成员-将开发一个原子模拟方法的调查课程，并开发生物分子模拟方法的重要“短期课程”。这些课程将为整合和突出PI的研究工作与教育工作提供具体的场所。此外，PI旨在招募代表性不足的学生加入研究小组，特别关注女性和西班牙裔。充分认识到国际合作对研究和教育的重要性，PI目前参与了两项单独的倡议，以建立一个外汇计划-一个与TU柏林和一个与阿根廷。更广泛的影响：研究部分影响定量生物学以及理论和计算材料研究领域。教育部分支持精通计算的世纪劳动力，并为代表性不足的群体提供机会。123456789012345678901234567890123456789012345678901234567890123456789012

This CAREER award supports research and education in computational biophysics. Research activities will focus on biomolecular applications, and build on methodological advances made by the PI in the treatment of long-range electrostatic interactions between biomolecules, as well as new multiscale developments. Specific research goals focus primarily on aspects of nucleic acid recognition, and on protein-protein interactions as they occur in the Ras superfamily of GTPases. Crucial cell processes such as DNA replication, repair and transcription, mRNA translation, viral RNA insertion, etc., all involve complex interactions between proteins and nucleic acids. A true, physics-based characterization of these interactions has remained elusive, because of their relatively small magnitude and their varied physical origins. These interactions determine the "recognition" contacts between molecules, which allow for site-specific binding proteins to choose the correct nucleic acid sequence from millions of possibilities. Similar concepts of complexity and technical difficulty apply to protein-protein interactions. As a particular model for investigation with large-scale biomolecular simulations, the PI has chosen the family of GTPases, which act as molecular switches involved in signal transduction cascades and motility in mammalian cells. Additionally, the PI will also investigate the properties of selected organic solvents for the determination of protein surface binding sites. Experimentally, it has been established that the structure of many proteins solvated in a variety of organic solvents is almost identical to that in an aqueous environment. So, organic solvents allow experimentalists to probe the binding sites of proteins via the multiple solvent crystal structure (MSCS) method. Currently, there is little theoretical understanding of the properties of proteins solvated with organic molecules, which therefore represents an important opportunity for research. The PI plans to carry out these investigations in consultation and collaboration with other researchers at NC State and at a local NIH laboratory.The PI will focus on teaching two courses that showcase the power of biomolecular simulations and the applications outlined under this CAREER proposal. These courses aim to satisfy local needs for a survey course on atomistic simulation methods and an intense "short-course" on biomolecular simulations. These courses will form part of the educational effort of the Center for High Performance Supercomputing (CHiPS). Plans to recruit students from underrepresented groups, especially women and hispanics, and to participate in international collaborations are integrated into research and education activities. Broader impacts: The research component impacts the fields of quantitative biology as well as theoretical and computational materials research. The education component supports a computationally able 21st century workforce and provides opportunities for members of underrepresented groups.%%%This CAREER award supports an integrated research and education plan in the area of Computational Biophysics. Based on recent algorithmic advances combined with the growing power of parallel computing, it is now becoming possible to directly investigate the action of biomolecules with the power of molecular dynamics simulations. The PI's research will primarily focus on: (i) organic solvents for the determination of protein surface properties; (ii) DNA sequence-dependent structure in solution; (iii) protein-protein interactions as they occur in the Ras superfamily of GTPases. The investigations of these systems will all represent an important step in enhancing our understanding of fundamental biomolecular processes. The educational goals of this CAREER proposal, are based on the concept of a "multiscale" education for graduate students which is to take place under the auspices of a newly developed Center aimed at fostering high performance supercomputing, i.e., an education that ensures that students have a broad set of computational simulation skills at their disposal, rather than being focused on a narrow field. To this end, the PI - who is an active member of the Center-will develop a survey course on atomistic simulation methods and develop important "short courses" on biomolecular simulation methods. These courses will provide specific venues for integrating and highlighting the research efforts of the PI with the educational effort. In addition, the PI aims to work on recruiting underrepresented students into the research group, with a particular focus on women and hispanics. Fully recognizing the importance of international collaborations for both research and education, the PI is currently involved in two separate initiatives to set up a foreign exchange program - one with the TU-Berlin and one with Argentina. Broader impacts: The research component impacts the fields of quantitative biology as well as theoretical and computational materials research. The education component supports a computationally savvy 21st century workforce and provides opportunities for members of underrepresented groups.***123456789012345678901234567890123456789012345678901234567890123456789012