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Hai Lin和Emilie Guidez将开发和应用新型计算算法来研究离子如何通过膜蛋白NarK进行运输。NarK蛋白将硝酸盐（必需元素氮的矿物形式）输入细胞，并将亚硝酸盐（高浓度时可能有毒的代谢物）输出细胞。然而，NarK蛋白的机制仍然知之甚少。准确和高效的计算机建模和模拟是非常需要的，以提供关键的见解。Lin和Guidez将制定新的多尺度算法，无缝地将联合收割机量子和经典建模技术结合起来，并利用这些算法，他们的研究小组将着手挖掘关于NarK如何帮助离子穿过细胞膜的原子细节。这项合作研究有可能从根本上推进对膜转运蛋白营养摄取的理解，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疾病的新疗法。科罗拉多大学丹佛分校既是一个西班牙裔服务机构（HSI），也是一个亚裔美国土著太平洋岛民服务机构。Lin和Guidez将积极招募来自代表性不足的群体的学生，以直接或通过EUReCA促进多样性！和XSEDE EMPOWER计划。此外，他们将扩大与樱桃溪高中非常成功的合作伙伴关系，包括樱桃溪创新校园，在那里高中教师将通过每年的夏季研究计划参与实践研究。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。NarK运输机的运行机制多年来一直难以捉摸。例如，诱变实验已经揭示，具有离域π键的结合位点残基对于转运活性是必不可少的，但它们究竟如何影响底物募集和易位仍然未知。Lin和Guidez将开发新的自适应分区多层方法，这些方法是下一代ONIOM类方法，具有动态重新定位的层间边界。新算法有望实现高度准确和高效的动力学模拟，以解开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可能改变许多通道和转运蛋白的离子迁移研究。通过一系列夏季外展项目，该项目将为K-12教师和学生提供绝佳的机会，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NSF的法定使命，并通过使用基金会的智力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.