CAREER:Free Energies of Protein Partitioning and Membrance Pertubations

职业：蛋白质分配的自由能和膜扰动

• 批准号: 0546768
• 负责人: Toby Allen
• 金额: $ 77.46万
• 依托单位: University of California-Davis
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-15 至 2011-03-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0546768&HistoricalAwards=false
• 关键词: CAREER; Free; Energies; Protein; Partitioning

A quantitative measure and molecular-level interpretation of protein-lipid interactions is essential to understand the partitioning, folding and function of membrane-proteins, which make up 20-30% of the human genome. Furthermore, understanding the physical rules that govern the assembly of membranes with their associated proteins is important for future developments in integrated biomembrane nano-devices. Experiment has provided a wealth of valuable information about protein-membrane interaction. Modern computer simulation can complement these experiments, strengthen our microscopic understanding and resolve some unanswered questions. A rigorous statistical mechanical framework is invoked here to capture the free energies governing protein structure and function in a membrane environment. These free energy calculations will push the boundaries of state of the art simulation. Despite the challenges, Dr. Allen has devised a realizable strategy employing polypeptides as model transmembrane segments to elucidate the general mechanisms of protein-lipid interaction. To begin, microscopic simulations will provide a free energy profile of an amino acid, attached to a transmembrane segment, and reveal bilayer perturbations as a function of depth. Such information is unattainable with experiment, yet essential to understand how the stability of a membrane-protein is determined by the specific arrangement of amino acids in the three-dimensional protein structure. The principle of 'hydrophobic matching' has been used to help explain the insertion and folding of proteins, protein activity, lipid micro-domain formation and protein aggregation. Dr. Allen details a series of new and innovative umbrella sampling and free energy perturbation calculations that directly tackle the thermodynamics governing mismatch. Dr. Allen's dedication to university and community is evidenced by his contributions and innovations in teaching and outreach activities. A revamped Computational Chemistry course will tie in both Dr. Allen's previous teaching and current research so that students, theoretical or experimental, learn the skills needed to pursue projects and critically assess published results. Dr. Allen is actively seeking new and exciting ways of harnessing the curiosity and enthusiasm of young and underprivileged students and encouraging them to pursue careers in science. He will co-organize and mentor in the ACS 'SEED' program at UCD which is designed to create opportunities for high school students from economically disadvantaged backgrounds. He is working with the COSMOS program (http://cosmos.ucdavis.edu) to develop a 4-week course suitable for high-school students and is also developing his own initiative, 'Careers in Chemical and Biological Simulation', that will bring together scientists from university and industry to provide students with exciting opportunities in chemical and biological simulation.

蛋白质-脂质相互作用的定量测量和分子水平的解释对于理解膜蛋白的分配，折叠和功能至关重要，膜蛋白占人类基因组的20-30%。此外，了解的物理规则，管理组件的膜与其相关的蛋白质是重要的未来发展的集成生物膜纳米器件。实验为蛋白质-膜相互作用提供了大量有价值的信息。现代计算机模拟可以补充这些实验，加强我们的微观理解，并解决一些悬而未决的问题。一个严格的统计力学框架在这里调用捕获自由能在膜环境中的蛋白质结构和功能。这些自由能计算将推动最先进的模拟边界。尽管面临挑战，艾伦博士已经设计出一种可实现的策略，采用多肽作为模型跨膜片段，以阐明蛋白质-脂质相互作用的一般机制。开始，微观模拟将提供一个氨基酸的自由能分布，连接到一个跨膜段，并揭示双层扰动作为深度的函数。这些信息是无法通过实验获得的，但对于理解膜蛋白的稳定性如何由三维蛋白质结构中氨基酸的特定排列决定至关重要。“疏水匹配”原理已被用来帮助解释蛋白质的插入和折叠、蛋白质活性、脂质微区形成和蛋白质聚集。艾伦博士详细介绍了一系列新的和创新的伞采样和自由能微扰计算，直接解决热力学管理失配。艾伦博士对大学和社区的奉献精神体现在他在教学和推广活动中的贡献和创新。改进后的计算化学课程将结合艾伦博士以前的教学和目前的研究，使学生，理论或实验，学习所需的技能，追求项目和批判性地评估发表的结果。艾伦博士正在积极寻求新的和令人兴奋的方式来利用年轻和贫困学生的好奇心和热情，并鼓励他们追求科学事业。他将在UCD的ACS“种子”计划中共同组织和指导，该计划旨在为来自经济弱势背景的高中生创造机会。他正在与COSMOS计划（http：//www.example.com）合作，开发适合高中生的为期4周的课程，并正在开发自己的倡议，“化学和生物模拟职业”，这将汇集来自大学和工业界的科学家，为学生提供化学和生物模拟方面令人兴奋的机会。cosmos.ucdavis.edu