Adaptive Multi-Layer Simulations of NarK Transport Protein

在化学系化学理论、模型和计算方法项目的资助下，科罗拉多大学丹佛分校的Lin和Emilie Guidez将开发并应用新的计算算法来研究离子如何通过膜蛋白NarK运输。NarK蛋白将硝酸盐（必需元素氮的一种矿物质形式）输入细胞，并将亚硝酸盐（一种高浓度有毒的代谢物）输出细胞。然而，对NarK蛋白的机制仍知之甚少。准确和高效的计算机建模和模拟是非常需要提供关键的见解。Lin和Guidez将制定新的多尺度算法，将量子和经典建模技术无缝结合，并利用这些算法，他们的研究小组将着手揭示NarK如何帮助离子穿越细胞膜的原子细节。这项合作研究有可能从根本上促进对膜转运体营养摄取的理解，因此，从长远来看，可能有助于开发与这些蛋白质功能障碍相关的疾病的新疗法。科罗拉多大学丹佛分校既是一所拉美裔服务机构（HSI），也是一所亚裔美国原住民太平洋岛民服务机构。林和guidz将积极从代表性不足的群体中招收学生，以促进多样性，无论是直接还是通过EUReCA！和XSEDE EMPOWER计划。此外，他们还将扩大与樱桃溪高中（Cherry Creek High School）非常成功的合作伙伴关系，包括樱桃溪创新校园（Cherry Creek Innovation Campus），在那里，高中教师将通过每年的夏季研究项目参与动手研究。这些外展活动将促进K-12课程创新，并探索学生对STEM（科学、技术、工程和数学）领域研究的兴奋。多年来，关于NarK转运体的运作机制一直是一个谜。例如，诱变实验表明，具有离域pi键的结合位点残基对转运活动至关重要，但它们究竟如何影响底物招募和易位仍然未知。Lin和Guidez将开发新的自适应划分多层方法，这是下一代具有动态重新定位层间边界的类似onom的方法。新算法有望实现高度精确和高效的动力学模拟，以解锁NarK中阴离子结合和易位的分子细节。新的模拟工具和该项目产生的机制见解都有可能改变许多通道和转运体离子迁移的研究。通过一系列的暑期推广项目，该项目将为K-12教师和学生提供极好的机会，让他们接触现代计算机建模技术，并积极参与生化研究。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

With funding from the Chemical Theory, Models and Computational Methods program in the Division of Chemistry, Hai Lin and Emilie Guidez of the University of Colorado-Denver will develop and apply novel computational algorithms to study how ions are transported through the membrane protein NarK. The NarK protein imports nitrate (a mineral form of the essential element nitrogen) into the cell and exports nitrite (a metabolite that can be toxic in high concentrations) out of the cell. However, the mechanism of the NarK protein remains poorly understood. Accurate and efficient computer modeling and simulations are highly desired to provide critical insights. Lin and Guidez will formulate new multiscale algorithms that seamlessly combine quantum and classical modeling techniques, and employing these algorithms, their research groups will set forth to unearth the atomistic details on how NarK helps the ions travel across the cell membranes. This collaborative research has the potential to fundamentally advance understanding of nutrient uptake by membrane transporters and, consequently, in the longer term, potentially assist in the development of novel therapies for diseases related to these protein malfunctions. The University of Colorado-Denver is both a Hispanic-Serving Institution (HSI) and an Asian American Native American Pacific Islander-Serving Institution. Lin and Guidez will actively recruit students from underrepresented groups to promote diversity, both directly and through the EUReCA! and XSEDE EMPOWER programs. In addition, they will expand the highly successful partnership with Cherry Creek High School to include Cherry Creek Innovation Campus, where high-school teachers will participate in hands-on research through a yearly summer research program. These outreach activities will promote K-12 curriculum innovation and explore students to the excitement of research in STEM (science, technology, engineering and mathematics) fields.The operation mechanism of the NarK transporter has remained elusive for many years. For example, mutagenesis experiments have revealed that the binding-site residues with delocalized pi bonds are essential to the transport activities, but exactly how they influence substrate recruitment and translocation remains unknown. Lin and Guidez will develop novel adaptive-partitioning multi-layer methods that are next-generation ONIOM-like methods with on-the-fly relocated interlayer boundaries. The new algorithms are expected to enable highly accurate and efficient dynamics simulations to unlock the molecular details of anion binding and translocation in NarK. Both the new simulation tools and the mechanistic insights resulting from this project can potentially transform the study of ion migration for many channels and transporters. Through a series of summer outreach programs, this project will provide excellent opportunities to get K-12 teachers and students by exposing them to modern computer modeling techniques, and actively engaging them in biochemical research.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.