CAREER: Implicit Modeling of Nonpolar Solvation: Towards Reliable Atomistic Simulation of Intrinsically Disordered Proteins

职业：非极性溶剂化的隐式建模：实现本质无序蛋白质的可靠原子模拟

• 批准号: 0952514
• 负责人: Jianhan Chen
• 金额: $ 67.24万
• 依托单位: Kansas State University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0952514&HistoricalAwards=false
• 关键词: CAREER; Implicit; Modeling; Nonpolar; Solvation

Accurate atomistic simulation of large conformational changes of proteins remains one of the greatest challenges in computational biology. Implicit treatment of the solvent environment has recently emerged as the premier alternative to traditional explicit solvent with a desired balance between accuracy and speed. The objective of this CAREER project is to develop, optimize and assess novel implicit treatments of nonpolar solvation to better balance competing electrostatic and nonpolar interactions. The second objective is to combine simulation and experiment to understand the structure, interaction and control of intrinsically disordered proteins (IDPs). IDPs are an important newly recognized class of functional proteins that rely on a lack of stable structures for function. The heterogeneous and dynamic nature of IDPs presents significant challenges for detailed characterization with either experiment or simulation alone. The PI will combine implicit solvent modeling, advanced sampling techniques, and NMR experiment to address these challenges. A novel hypothesis to be tested is that long- range electrostatic interactions can act concertedly with fly-casting to facilitate efficient recognition of IDPs. New and fundamental information will be obtained on the molecular principles of IDP structure and interaction. A practical outcome of this project will be an improved implicit solvent protein force field that can be broadly applied to study protein structure, dynamics and interaction.The new protein modeling tools will be directly incorporated into training and educational activities including practical course units, training projects involving undergraduate and high school students, and summer workshops for a diverse selection of participants. Specifically, the PI will: 1) develop and revamp undergraduate and graduate courses to increase interdisciplinary awareness at an early stage of education and to provide basic training in biomolecular simulation that is much needed at Kansas State University (KSU); 2) continue to actively contribute to outreach programs at KSU including Women in Engineering and Science Program, Developing Scholar Program and Bridges to the Baccalaureate to increase the participation of women and other minorities in science; 3) initiate annual two-day summer workshops to enhance the knowledge of computational and structural biology for college and high school teachers. Special emphasis will be placed on recruiting teachers from community colleges in southern Kansas that have a large Hispanic student population and traditionally show weakness in student preparation. These workshops will help foster new collaborations in research and education with minority-severing institutions.

蛋白质大构象变化的精确原子模拟一直是计算生物学中最大的挑战之一。溶剂环境的隐式处理最近已成为传统显式溶剂的首要替代方案，具有准确性和速度之间的理想平衡。这个CAREER项目的目标是开发，优化和评估新的隐式处理非极性溶剂化，以更好地平衡竞争的静电和非极性相互作用。第二个目标是将联合收割机模拟和实验相结合，以了解内在无序蛋白质（IDP）的结构，相互作用和控制。IDP是一类重要的新认识的功能蛋白，其依赖于缺乏稳定的功能结构。IDPs的异质性和动态性提出了重大的挑战，无论是实验或模拟单独的详细表征。PI将结合联合收割机隐式溶剂建模，先进的采样技术和NMR实验来解决这些挑战。待测试的新假设是，长程静电相互作用可以与飞投协同作用以促进对IDP的有效识别。将获得关于IDP结构和相互作用的分子原理的新的和基本的信息。该项目的一个实际成果将是一个改进的隐式溶剂蛋白质力场，可广泛应用于研究蛋白质结构，动力学和相互作用。新的蛋白质建模工具将直接纳入培训和教育活动，包括实践课程单元，涉及本科生和高中生的培训项目，以及为不同参与者选择的夏季研讨会。具体而言，PI将：1）开发和改进本科和研究生课程，以提高教育早期阶段的跨学科意识，并提供堪萨斯州立大学（KSU）急需的生物分子模拟方面的基本培训; 2）继续积极促进KSU的外联方案，包括妇女在工程和科学方案，发展学者计划和通往学士学位的桥梁，以增加妇女和其他少数族裔对科学的参与; 3）每年举办为期两天的暑期研讨会，以提高大学和高中教师的计算和结构生物学知识。将特别强调从堪萨斯南部的社区学院招聘教师，这些社区学院拥有大量西班牙裔学生，传统上在学生准备方面表现薄弱。这些讲习班将有助于促进与少数群体机构在研究和教育方面的新合作。