CAREER: Modeling and Analyzing High-Dimensional Molecular Assembly: Quantifying the Impact of Allergen Structure

该职业奖将整合致力于计算模拟和分子相互作用分析的研究和教育。分子的相互作用和结合是构建功能性超结构的关键。一个这样的过程，抗体和过敏原的分子组装是信号过敏反应的前兆。本项目将研究如何有效地捕获和分析多分子结合的复杂构象空间，以提供有关聚集体结构和组装的详细信息。该方法受高维机器人运动搜索的启发，将结合并集成分子结构的混合和多分辨率模型，装配路径和动力学的运动规划模拟，以及对过敏原结构和抗原组装影响的理解。这项工作将开发适用于一系列分子组装问题的工具。通过建模提供的几何洞察将能够快速测试组装诱导的过敏信号的中断，即过敏治疗。实验合作将允许直接利用和验证模型和工具，快速模拟可能为新的实验指明道路。该教育计划包括用于演示分子相互作用的分子组装触觉相互作用的开发和跨学科教育材料的设计。该职业将整合研究和教育，致力于装配过程的计算模拟和分析。这将通过四个研究重点来实现，这些研究重点将导致基于生物物理学、规划和随机过程技术的分子组装结构建模和分析的可调分辨率、计算效率和通用框架。该奖项的重点将是抗体-过敏原相互作用的模拟和分析。需要一个可调的分辨率模型，以实现低计算成本的模拟，通过有限的，但现实的，分子灵活性和混合分辨率结构。提出的研究重点是在初步工作中使用的基于多边形的模型的适应性，以及运动连杆的自主目标放置，以实现灵活性。为了实现装配过程的模拟和动力学分析，将设计新的启发式方法并将其集成到能够模拟高维构象空间运动的数据结构中。通过建模提供的几何洞察将能够快速测试致敏级联的破坏，从而导致过敏治疗。实验合作将允许直接利用和验证所提议的工作，并可能导致发展新的实验。此外，教育触觉分子组装模块将允许学生感知物理原子力之间的两个相互作用的分子。这与跨学科研究和新课程相结合，重点是将代表性不足的少数民族纳入研究。

This CAREER award will integrate research and education dedicated to computational simulation and analysis of molecular interactions. Molecular interactions and binding are critical to the construction of functional superstructures. One such process, molecular assembly of antibodies and allergens is a precursor to signaling allergic response. This project will study how to efficiently capture and analyze the complex conformational space of multi-molecular binding, with the goal to provide detailed information about the structure and assembly of aggregates. The method, inspired by high-dimensional robotic motion search, will incorporate and integrate hybrid and multi-resolution models of molecular structures, motion planning simulation for assembly pathways and kinetics, and understanding of the impact of allergen structure and antigen assembly. This work will develop tools that are applicable to a range of molecular assembly problems. Geometric insights provided by modeling will enable the rapid testing of disruptions to assembly-induced allergenic signaling, i.e., allergy treatments. Experimental collaborations will allow direct utilization and verification of models and tools, and rapid simulation may point the way to new experiments. The educational plan includes development of a molecular assembly haptic interaction for demonstrating molecular interaction and the design of cross-disciplinary educational materials.This CAREER will integrate research and education dedicated to the computational simulation and analysis of assembly processes. This will be achieved through four research thrusts that lead to a tunable-resolution, computationally-efficient, generic framework for the structural modeling and analysis of molecular assembly based on techniques in biophysics, planning, and stochastic processes. The focus of this award will be simulation and analysis of antibody-allergen interaction. A tunable resolution model is required that will enable low computational cost simulations achieved through limited, yet realistic, molecular flexibility and hybrid-resolution structures. The proposed research focuses on adaptations of polygon-based models used in preliminary work, and autonomous targeted placements of kinematic linkages to enable flexibility. To enable simulation and kinetics analysis of assembly processes, new heuristics will be designed and integrated into data structure shown capable of simulating motions in high-dimensional conformational spaces. Geometric insights provided by modeling will enable the rapid testing of disruptions to the allergenic cascade, thus leading to allergy treatments. Experimental collaborations will allow direct utilization and verification of the proposed work and may lead to the development of new experiments. In addition, an educational haptic m0olecular assembly module will permit students to perceive physically the atomic forces between two interacting molecules. This is coupled with interdisciplinary research and new courses, with an emphasis on the integration of underrepresented minorities in the research.