Development and Application of Multi-scale Modeling to Biomolecular Association

准确和及时的分子识别是所有生物过程的基础。在代谢组装（或拆卸）线中，顺序参与者被认为是共同定位的，以最大限度地提高最终产品从多步骤途径产生的速度。研究者建议通过计算模拟生物合成途径网络来理解，尽管细胞环境很复杂，结合伙伴如何能够找到彼此，以及生物合成途径通量如何最大化。通过与合作者的反复实验和计算，研究者将建模和预测酶活性（参与者）的共定位对途径通量的影响。这项工作的首要目标是开发一种软件，使人们能够准确地模拟分子伴侣如何在复杂的细胞环境中找到彼此。这项工作可以应用于生物传感器的开发，因为传感器也必须能够在拥挤和混乱的环境中检测到它们的特定目标。该项目还将有助于培养研究生和本科生。将组织一个夏季讲习班，培训当地社区学院、大学和高中的学生。分子结合是两个或多个分子必须找到彼此的过程，是所有生化催化和（生物）传感技术的第一个关键步骤。该项目结合了多层次的模拟、理论工作和实验合作来研究多酶系统中的分子识别和动力学增强。为了加快整体产物的合成速度，在设计多酶支架时可以考虑几个因素，包括几何形状、局部电荷分布和网络运动。生物传感器的设计是由目标和探针的结合机制决定的。该项目探索新颖的想法，并结合实验结果，原子分子动力学（MD）和布朗动力学（BD）模拟来研究多酶纳米结构和大规模膜结合生物传感器，无论是在体外还是在细胞样环境中。该结果为多酶和生物传感器系统提供了见解，将为工程和生物传感器设计提供信息。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。

Accurate and timely molecular recognition is fundamental to all biological processes. In metabolic assembly (or disassembly) lines, sequential participants are thought to co-localize to maximize the rate at which a final product can emerge from a multi-step pathway. The investigator proposes to computationally simulate biosynthetic pathway networks in an effort to understand how, despite the complexity of the cellular milieu, binding partners are able to find each other, and biosynthetic pathway flux can be maximized. Through iterations of experiments with collaborators and computation, the investigator will model and predict the effects of co-localization of enzyme activities (the participants) on pathway flux. The overarching goal of the work is to develop software that allows one to accurately simulate how molecular partners find each other in the complex environment of the cell. The work has application to biosensor development, as sensors must also be able to detect their specific targets in a congested and chaotic environment. The project will also contribute to the training of graduate and undergraduate students. A summer workshop will be organized to train students from local community colleges, universities and high schools. Molecular association, in which two or more molecules must find one another, is the first critical step for all biochemical catalysis and (bio)sensing techniques. The project combines multi-level simulations, theoretical work and experimental collaboration to investigate molecular recognition and kinetic enhancements in multi-enzyme systems. To accelerate the overall product synthesis rate, several factors may be considered in designing a multi-enzyme scaffold, including geometry, local charge distribution, and network motions. The design of biosensors is informed by the binding mechanisms of a target and probe. The project explores novel ideas and incorporates results from experiments, atomistic molecular dynamics (MD), and Brownian dynamics (BD) simulations to investigate multi-enzyme nanostructures and large-scale membrane bound biosensors, either in vitro or a cell-like environment. The results offer insight into multi-enzyme and biosensor systems that will inform engineering and biosensor design.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.