Exploring Receptor-mediated Endocytosis of Bioparticles through Multiscale Modeling

Pi：Liu，jin Propsal#：1604211通过受体介导的内吞作用(RME)，结合到细胞表面(内吞作用)的生物颗粒(如病毒和药物载体)的内化在基本了解病毒感染和靶向药物输送方面起着至关重要的作用。生物颗粒的RME是一个高度复杂和多尺度的过程，很难通过特定尺度的技术进行研究。这个为期三年的项目的目标是建立一个跨学科的研究计划，通过多尺度建模和模拟来研究生物颗粒的RME。模型模拟将用于1)进行能量计算，2)研究颗粒大小/形状、配体密度/类型和分子相互作用对整个过程的影响，以及3)探索在跨越血脑屏障的脑药物输送和预防单纯疱疹病毒方面的应用。这些发现将在病毒感染和使用纳米载体的细胞内/跨细胞靶向药物输送、营养摄取、基于对比成像和癌症进展/转移等领域产生广泛的科学和技术影响。结果可能导致合理的设计和工程，有效的药物输送和新的策略，病毒干预和抑制。通过夏令营、实验室体验和与当地科学中心的合作，学生将接受独特的跨学科培训，并为K-12提供机会，从而提高教育影响。该奖项由数学科学部的数学生物学项目通过BioMaps项目共同资助。生物制剂，如病毒和药物载体，通过受体介导的内吞作用(RME)内化在基本了解病毒感染和细胞内/跨细胞靶向给药方面发挥着至关重要的作用。生物颗粒的RME是一个高度复杂和多尺度的过程，很难通过特定尺度的技术(无论是实验还是数值)进行研究。这个为期三年的项目的目标是建立一个跨学科的研究计划，通过多尺度建模和模拟来研究生物颗粒的RME。本文的研究目标是：1)利用蒙特卡罗方法在曲线空间上离散Helfrich哈密顿量，将随机结合模型和介观膜模型相结合，建立生物微粒结合和内化的三维介观随机模型；2)实现粗粒度分子动力学模拟，研究RME中的分子事件，然后通过顺序和并发方法将原子模拟和介观模型耦合起来，建立多尺度模型；3)利用我们的多尺度模型进行自由能计算，考察颗粒大小/形状、配体密度/类型以及分子相互作用对RME整个过程的影响，探索其在血脑屏障给药和单纯疱疹病毒预防中的应用。通过考虑介观和原子效应的影响，多尺度模型将提供对这一过程的统一和连贯的描述。这些模拟将带来关键的、新的见解和对RME机制的更深层次的理解。该方案的创新包括：1)原子模拟与介观模型的集成，2)膜模型与随机结合模型的结合，使得能够探索具有极端变形的内吞作用，以及3)原子模拟中的粗粒度力场，使得能够捕捉RME过程中蛋白质-蛋白质相互作用的结构(构象)信息。多尺度模型与自由能计算一起，在不同的功能生物尺度之间建立了自然联系，并使模拟结果和实验数据之间能够直接和间接地关联。这些发现将在利用纳米载体的病毒感染和细胞内/跨细胞靶向药物输送、营养摄取、基于造影剂的成像和癌症进展/转移等领域产生广泛的科学和技术影响，结果可能导致有效药物输送的合理设计和工程，以及病毒干预和抑制的新策略。获得资助的学生将有机会接受机械工程和生物工程领域独特的跨学科培训，学习尖端的多尺度数值模拟技术，使他们成为生物/纳米技术领域的领导者。代表不足的少数族裔学生的参与将与现有的LSAMP和SWE项目协调。拟议研究的结果将通过西苏里州立大学的外联活动和与当地科学中心的合作向K-12年级的学生广泛传播，包括参加夏令营和创建3D可视化平台，用于以原子尺度分辨率对生物分子事件进行交互式探索和建模。

PI: Liu, JinPropsal #: 1604211Internalization of bioparticles bound to a cell's surface (endocytosis), such as viruses and drug carriers, through receptor-mediated endocytosis (RME) plays essential roles in fundamental understanding of viral infections and targeted drug deliveries. RME of bioparticles is a highly complex and multiscale process that is difficult to investigate through scale-specific techniques. The goal of this three-year project is to establish an interdisciplinary research program in investigating RME of bioparticles through multiscale modeling and simulations. Model simulations will be used 1) to make energy calculations, 2) to investigate the effects of particle size/shape, ligand density/type and molecular interactions on the overall process and 3) to explore applications in brain drug delivery across the blood-brain barrier and herpes simplex virus prevention. Findings will have broad scientific and technological impact in the fields of virus infection and intracellular/transcelluar targeted drug delivery using nanocarriers, nutrition uptake, contrast-based imaging and cancer progression/metastasis. Results may lead to a rational design and engineering for effective drug delivery and novel strategies for viral intervention and inhibition. Educational impact is advanced through the unique interdisciplinary training students will receive and opportunities provided for K-12 via summer camps, lab experiences and collaboration with a local science center. This award is cofunded by the Mathematical Biology program in the Division of Mathematical Sciences through the BioMaPs program. Internalization of bioparticles, such as viruses and drug carriers, through receptor-mediated endocytosis (RME) plays essential roles in fundamental understanding of viral infections and intracellular/transcellular targeted drug deliveries. RME of bioparticles is a highly complex and multiscale process, which is difficult to investigate through scale-specific techniques (both experimentally and numerically). The goal of this three-year project is to establish an interdisciplinary research program in investigating RME of bioparticles through multiscale modeling and simulations. The research objectives are: 1) to develop a 3D mesoscale stochastic model for binding and internalization of bioparticles, the mesoscopic model is a combination of a stochastic binding model with a mesoscopic membrane model based on the discretization of Helfrich Hamiltonian on a curvilinear space using Monte Carlo method; 2) to implement coarse-grained molecular dynamics simulations to investigate the molecular events in RME and then develop the multiscale model by coupling the atomistic simulations with the mesoscopic model through sequential and concurrent methods; and 3) to perform free energy calculations using our multiscale model and investigate the effects of particle size/shape, ligand density/type, as well as the molecular interactions on the overall process of RME, and explore the applications in brain drug delivery across blood-brain barrier and herpes simplex virus prevention. The multiscale model will provide a unified and coherent description of the process by accounting for effects from both mesoscopic and atomistic effects. The simulations will bring critical, new insight and a deeper understanding of the mechanism of RME. Innovations of the proposal include: 1) the integration of atomistic simulations with mesoscopic model, 2) the combination of the membrane model with the stochastic binding model that enables exploration of endocytosis with extreme deformations and 3) the coarse-grained force field in atomistic simulations that enables the capture of structural (conformational) information for protein-protein interactions during RME. The multiscale models, together with the free energy calculations, create natural links between different functional biological scales and enables direct and indirect correlations between modeling results and experimental data. Findings will have broad scientific and technological impact in the fields of virus infection and intracellular/transcelluar targeted drug delivery using nanocarriers, nutrition uptake, contrast-based imaging and cancer progression/metastasis and results may lead to a rational design and engineering for effective drug delivery, and novel strategies for viral intervention and inhibition. The students supported by the grant will have opportunities to receive a unique interdisciplinary training across the mechanical engineering and bioengineering, learn the cutting-edge multiscale numerical modeling techniques, which enable them to become leaders in the bio/nanotechnology field. The involvement of under-represented minority students will be coordinated with existing LSAMP and SWE programs. The findings from the proposed research will be broadly disseminated to K-12 students through outreach activities in WSU and collaboration with local science center, including participation in summer camps and creation of a 3D visualization platform for interactive exploration and modeling of biomolecular events with atomic-scale resolution.