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

精确的原子模拟蛋白质的大的构象变化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已成为传统显式溶剂的首选替代方法，在准确度和速度之间取得了理想的平衡。这个职业项目的目标是开发、优化和评估非极性溶剂化的新的隐式处理方法，以更好地平衡相互竞争的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质(IDPs)的结构、相互作用和控制。内毒素是一类重要的新发现的功能蛋白，其功能依赖于缺乏稳定的结构。国内流离失所者的异质和动态性质给仅凭实验或模拟进行详细描述带来了重大挑战。PI将结合隐含的溶剂建模、先进的采样技术和核磁共振实验来解决这些挑战。一个有待检验的新假设是，远程静电相互作用可以与飞投协同作用，以促进对国内流离失所者的有效识别。将获得有关IDP结构和相互作用的分子原理的新的和基本的信息。该项目的实际成果将是改进的隐含溶剂蛋白质力场，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，包括实用课程单元、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暑期研讨会。具体地说，PI将：1)开发和改革本科和研究生课程，以提高学生在早期教育阶段的跨学科意识，并提供堪萨斯州立大学(KSU)亟需的生物分子模拟方面的基础培训；2)继续积极促进堪萨斯州立大学的外联项目，包括妇女参与工程和科学计划，制定奖学金计划和通向文凭的桥梁，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讲习班，以增强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州南部的社区大学招聘教师，这些大学拥有大量拉美裔学生，传统上在学生准备方面表现出弱点。这些讲习班将有助于促进与支持少数群体的机构在研究和教育方面开展新的合作。

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.