Predicting the Nature of the Protein Corona: From Fundamental Modeling to Phenomenological Descriptors

对纳米技术在电子、材料、医学和能源领域革命性发展潜力的兴奋，被对工程纳米材料对环境和人类健康影响的担忧所冲淡。纳米材料的小尺寸使其对创造新的分子级工程设备如此有吸引力，这使得它们非常容易通过吸入、摄入和皮肤渗透被人体吸收。先前的研究表明，毒性与纳米颗粒的物理化学性质有关，如尺寸、形状、表面积、电荷、团聚状态和疏水性，但尚未确定一般趋势。我们的研究是基于目前的想法，即身体对纳米颗粒入侵的反应的关键步骤是蛋白质冠的形成，蛋白质冠是一种包围纳米颗粒的包膜，其中含有在初始暴露后从生物流体中吸附的蛋白质。拟议研究的长期目标是开发一种能够预测工程纳米材料上蛋白质冠的性质和组成的相关工具。 这项研究旨在成为开发纳米颗粒风险评估模型的第一步。后续步骤将与合作者一起完成，他们计划使用相关性来帮助预测纳米材料的体内处置（ADME），开发基于生理学的药代动力学（PBPK）模型并最终创建风险评估模型。智力优势：目标是：（1）预测生物流体中的哪些蛋白质粘附到特定的工程纳米材料上，（2）提供一组描述符，表征给定工程纳米材料冠的组成和物理化学性质，以及（3）使用这些工具对蛋白质对特定纳米颗粒的亲和力进行排序。多尺度建模将用于确定一个新的中间分辨率模型，“PRIME/NP”蛋白质/纳米颗粒系统的几何和能量参数。基于PRIME/NP的能量计算将用于预测纳米颗粒/蛋白质亲和力，不连续分子动力学（DMD）模拟将用于模拟蛋白质在纳米颗粒上的竞争吸附。更广泛的影响：拟议的研究可能会影响生物材料领域的研究，其中医疗植入物的生物相容性是一个问题。除了培养一名（女）博士生外，还将通过以下方式促进研究和教育：（1）使用纳米颗粒蛋白质冠的形成，它与工程纳米材料的潜在毒性的关系，以及政府和社会对这个问题的反应作为PI的本科化学工程热力学课程开发的例子的基础，（2）制作一个介绍纳米技术和毒性测量基本知识的powerpoint演示文稿，通过网络传播，以及（3）制作针对普通观众的视频演示，展示分子-水平的计算机模拟可用于了解纳米颗粒的毒性PI将继续她可观的，但非正式的活动，以扩大妇女的机会，并将介绍一个棕色袋午餐系列的女研究生和博士后她在NCSU的部门

Abstract#1236053Hall, Carol K.Excitement about the potential of nanotechnology to revolutionize the fields of electronics, materials, medicine, and energy is tempered by concerns about the impact of engineered nanomaterials on the environment and on human health. The small sizes that make nanomaterials so attractive for the creation of new molecular-scale engineering devices render them highly susceptible to adsorption by the human body through inhalation, ingestion and skin penetration. Previous studies suggest that toxicity is related to the physicochemical properties of nanoparticles such as size, shape, surface area, charge, agglomeration status, and hydrophobicity but no general trends have been established. Our research is based on the current thinking that a key step in the body's response to nanoparticle intrusion is the formation of the protein corona, an envelope surrounding the nanoparticle containing proteins adsorbed from the biological fluid following initial exposure. The long term goal of the proposed research is to develop a correlation tool capable of predicting the nature and composition of the protein corona on engineered nanomaterials. This research is intended to be the first step in the development of risk assessment models for nanoparticles. Subsequent steps will be done with collaborators who plan to use the correlation to help predict the in vivo disposition (ADME) of nanomaterials, develop physiologically- based pharmacokinetic (PBPK) models and ultimately create risk assessment model. Intellectual Merit: The objectives are: (1) to predict which proteins in biological fluids adhere to specific engineered nanomaterials, (2) to provide a set of descriptors that characterize the composition and physico-chemical properties of the corona of a given engineered nanomaterial, and (3) to use these tools to rank order the affinities of proteins for specific nanoparticles. Multiscale modeling will be used to determine geometric and energetic parameters for a new intermediate-resolution model, "PRIME/NP" for protein/nanoparticle systems. Energy calculations based on PRIME/NP will be used to predict nanoparticle/protein affinities, and discontinuous molecular dynamics (DMD) simulations will be used to model competitive adsorption of proteins on nanoparticles.Broader Impacts: The proposed research could impact research in the area of biomaterials where the biocompatibility of medical implants is an issue. In addition to training a (female) Ph.D student, research and education will be fostered by: (1) using nanoparticle-protein corona formation, its relation to the potential toxicity of engineered nanomaterials, and the response to this issue by government and society as the basis for examples developed for the PI's undergraduate chemical engineering thermodynamics course, (2) creating a power-point presentation describing the basics of nanotechnology and measurement of toxicity for dissemination via the web, and (3) making a video presentation targeted for general audiences that shows how molecular-level computer simulation can be used to understand nanoparticle toxicity The PI will continue her considerable but informal activities to broaden the opportunities for women and will introduce a brown bag lunch series for women graduate students and postdocs in her department at NCSU.