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

精确的蛋白质大构象变化的原子模拟仍然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成为传统显式溶剂的首选替代方案，在准确性和速度之间取得了理想的平衡。本CAREER项目的目标是开发、优化和评估新的非极性溶剂化隐式处理，以更好地平衡静电和非极性相互作用。第二个目标是将模拟和实验相结合，以了解内在无序蛋白（IDPs）的结构、相互作用和控制。IDPs是一类重要的新认识的功能蛋白，依赖于缺乏稳定的结构来实现功能。IDPs的异质性和动态性对仅通过实验或模拟进行详细表征提出了重大挑战。PI将结合隐式溶剂建模、先进的采样技术和核磁共振实验来解决这些挑战。一个有待验证的新假设是，远距离静电相互作用可以与飞投协同作用，以促进对IDPs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。本项目的实际成果将是一个改进的隐式溶剂蛋白力场，可广泛应用于蛋白质结构、动力学和相互作用的研究。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，以及面向不同参与者的夏季讲习班。具体而言，PI将：1)开发和改进本科和研究生课程，以提高早期教育阶段的跨学科意识，并提供堪萨斯州立大学（KSU）急需的生物分子模拟的基础培训；2)继续积极参与KSU的外展项目，包括工程和科学领域的女性项目，发展学者项目和通往学士学位的桥梁，以增加女性和其他少数民族在科学领域的参与；3)每年举办为期两天的夏季研讨会，以提高大学和高中教师的计算和结构生物学知识。特别的重点将放在从堪萨斯州南部的社区大学招聘教师，那里有大量的西班牙裔学生，传统上在学生准备方面表现得很弱。这些讲习班将有助于促进与少数民族隔离机构在研究和教育方面的新合作。

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.