DMREF: Accelerated discovery of metastable but persistent contact insecticide crystal polymorphs for enhanced activity and sustainability

非技术描述：世界卫生组织估计，疟疾和其他媒介传播的传染病，如寨卡病毒或登革热，每年在全球造成70多万人死亡。防治疟疾的一个重要组成部分是通过使用室内残留喷洒接触性杀虫剂和驱虫蚊帐来控制病媒。接触式杀虫剂是有机结晶材料的粉末。当蚊子停留在粉末颗粒上时，它们会通过脚吸收这种活性物质，从而产生致命的效果。纽约大学的研究人员先前证明，接触性杀虫剂的功效在很大程度上取决于它们的晶体形式，也就是所谓的多晶型，它们具有相同的分子组成，但不同的晶体结构。更活跃的多晶型也必须在其应用的持续时间内表现出对抗转换为不活跃多晶型的高稳定性。该项目的中心目标是通过计算和实验，以知识为导向设计具有优越性能的亚稳晶体形式，以实现其目标应用。在使用接触式杀虫剂的情况下，这将减少有毒物质的使用，减少对环境的影响，从而在多个方面实现关键的可持续性目标。各种研讨会，包括儿童计算机晶体，儿童机器学习和水晶万花筒，将向K-12学生传达项目的科学知识。通过大学科学技术入学计划，将特别关注黑人、拉丁裔和美洲原住民学生。技术说明：通过创新接触性杀虫剂配方，将分子晶体亚稳态多形物应用于疟疾和登革热等病媒传播疾病的管理，这是一个新的、可持续的机会目标。加速发现这种低热力学但高动力学稳定性的亚稳态多晶是一项关键挑战，只能通过紧密集成的计算和实验工作流程来满足。从世界卫生组织批准用于室内残留喷洒的12种已知接触性杀虫剂（包括拟除虫菊酯、有机磷酸酯、氨基甲酸酯和新烟碱类杀虫剂）开始，该项目将探索符合上述标准的晶体多形物的创新方法，这对于在室内残留喷洒应用和杀虫剂处理过的蚊帐中依赖于昆虫tarsi与晶体表面物理接触的杀虫剂效果至关重要。实验上，这些亚稳多晶可以从熔体或溶液中获得，通过（交叉）成核、相变或在纳米约束下生长。实验工作将由一个理论框架的发展来补充，该理论框架的重点是由热力学和动力学因素驱动的能量可接近的多晶的形成，以及不同多晶之间的转换及其表面性质。这些任务超出了标准计算工具的范围，需要开发新的理论方法，将增强的分子模拟和机器学习的力量结合起来。初步计算结果将通过实验数据进行验证，以完善理论框架。同样，理论预测将用于指导和完善实验方案。这种相互反馈的迭代循环最终将汇集到全面可靠的工作流程中，这将加速具有特殊特性的亚稳态多态性的发现和开发，与材料基因组计划的目标一致。各种研讨会，包括儿童计算机晶体，儿童机器学习和水晶万花筒，将向K-12学生传达项目的科学知识。通过大学科学技术入学计划，将特别关注黑人、拉丁裔和美洲原住民学生。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。

Non-technical Description: The World Health Organization estimates that malaria and other vector-borne infectious diseases, such as Zika or dengue fever, are responsible for more than 700,000 deaths worldwide annually. An essential component in the fight against malaria is the control of disease vectors through the use of contact insecticides for indoor residual spraying and insecticide-treated nets. Contact insecticides are powders of organic crystalline materials. As mosquitoes rest on the powder particles, they absorb the active substance through their tarsi (feet) to lethal effect. New York University investigators previously demonstrated that the efficacy of contact insecticides strongly depends on the identity of their crystalline forms, otherwise known as polymorphs, which have identical molecular compositions but different crystal structures. The more active polymorphs must also exhibit a high stability against transformation to less active polymorphs for the duration of their application. The central objective of this project is a knowledge-guided design, through computation and experiment, of metastable crystalline forms with superior properties for their target application. In the context of contact insecticides, this will allow less toxicant to be used, reduce environmental impact, and, thereby, meet key sustainability goals on multiple fronts. Various workshops, including Computer Crystals for Kids, Machine Learning for Kids, and Crystal Kaleidoscope, will convey the science of the project to K-12 students. Special attention will be provided to engage Black, Latino, and Native American students through the Collegiate Science Technology Entry Program.Technical Description: The application of metastable polymorphs of molecular crystals in the management of vector-borne diseases such as malaria and dengue fever through innovations in contact insecticide formulations represents a new and sustainable target of opportunity. Accelerated discovery of such metastable polymorphs with low thermodynamic yet high kinetic stability constitutes a key challenge that can only be met using a tightly integrated computational and experimental workflow. Starting with twelve known contact insecticides approved by the World Health Organization for indoor residual spraying (including pyrethroids, organophosphates, carbamates, and neonicotinoids), the project will explore innovative approaches to crystal polymorphs that meet the aforementioned criteria, which are essential to insecticide efficacy that relies on physical contact between insect tarsi and crystal surfaces in indoor residual spraying applications and insecticide-treated nets. Experimentally, these metastable polymorphs can be obtained from melt or solution, by (cross-)nucleation, phase transformations, or growth under nanoconfinement. The experimental work will be complemented by the development of a theoretical framework focused on the formation of energetically accessible polymorphs – driven by both thermodynamic and kinetic factors – as well as the transformation between different polymorphs and their surface properties. These tasks are beyond the reach of standard computational tools, requiring the development of new theoretical methodologies that combine the strength of enhanced molecular simulations and machine learning. Initial computational results will be validated by experimental data to improve the theoretical framework. Similarly, theoretical predictions will be used to guide and refine experimental protocols. This iterative loop of mutual feedback will eventually converge toward comprehensive and reliable workflows that will accelerate the discovery and development of metastable polymorphs with exceptional properties, in accord with the goals of the Materials Genome Initiative. Various workshops, including Computer Crystals for Kids, Machine Learning for Kids, and Crystal Kaleidoscope, will convey the science of the project to K-12 students. Special attention will be provided to engage Black, Latino, and Native American students through the Collegiate Science Technology Entry Program.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.