CAREER: Multiscale Study of the Structure and Dynamics of Nanoparticle-Protein Coronae

建议：1553945PI：丁峰随着纳米技术的快速发展，工程纳米颗粒可能有意或无意地释放到环境和生物系统中。许多富含在环境和生物介质中的蛋白质作为功能构建块，可以被吸附到NP表面，形成所谓的NP-蛋白质电晕。是冠状蛋白质而不是原始的NPs被细胞和组织“看到”，并随后决定这些释放的NPs的生物学和/或病理功能。这项建议的目的是开发和应用最先进的计算机模拟方法来了解电晕形成的基本方面，并确定决定蛋白质吸收的NPs的物理和化学性质。所获得的知识将有助于指导新型NPs的设计，以促进预期的生物功能并防止意外的病理反应，使广泛的科学和工程界能够进行安全的设计，以建模和预测电晕形成并快速评估NP暴露的风险。在这份职业建议书中，PI建议应用多尺度离散分子动力学(DMD)方法来表征NP-蛋白质电晕的结构和动力学，并确定NP-蛋白质相互作用的物理化学决定因素。这项研究的目标将通过追求以下具体目标来实现：1)开发用于DMD模拟的NP模型及其与生物分子的相互作用；2)揭示NP-蛋白质结合的物理化学决定因素；3)表征蛋白质在日冕中聚集的结构和动力学；以及4)将课堂和实验室的研究和教育更广泛地扩展到其他教育和科学研究领域。开发和验证的计算方法将与广泛的科学研究界分享。拟议的研究项目将在分子和原子水平上揭示NP-蛋白质日冕的结构和动力学性质，并确定分子复合体形成的物理化学决定因素。这些机制研究的结果将对设计更有效、更安全、具有最佳性能的NPs具有关键作用，以促进预期的生物学功能，并将NP暴露的病理影响降至最低。这一提议的更广泛影响包括纳米技术的可持续发展和改善纳米医学的应用。这项研究的资金还将支持学生在物理、材料科学、生物和环境科学与工程的界面上进行培训，更新物理课程以反映当前的科学趋势，并增加物理教育和研究的多样性。这项拟议的研究将开发和验证关键的预测工具，以有效和高效地模拟纳米生物界面，可用于设计具有新生物功能的NPs，以及用于NP风险评估。此外，所开发工具的易获得性和增强的可用性将使在该领域工作的广大科学和工程界受益。

Proposal: 1553945PI: Ding, Feng With the rapid development of nanotechnology, engineered nanoparticles (NPs) may be released to the environmental and biological systems either purposely or accidentally. With many proteins enriched in the environmental and biological media as the functional building blocks, they can be absorbed onto the NP surface, forming the so-called NP-protein corona. It is the protein coronae rather than the original NPs that are "seen" by cells and tissues and subsequently determine the biological and/or pathological functions of these released NPs. The objective of this proposal is to develop and apply state-of-the-art computer simulation methods to understand the fundamental aspects of the corona formation and to determine the physical and chemical properties of NPs that dictate the protein absorption. The obtained knowledge will help guide the design of novel NPs that promotes the intended biological functions and prevents the unintended pathological responses, enabling the "safe-by-design" to the broad scientific and engineering community for modeling and predicting corona formation and rapid risk assessment of NP exposures. In this CAREER proposal, the PI proposes to apply the multiscale discrete molecular dynamics (DMD) methodology to characterize the structure and dynamics of NP-protein corona and to identify the physicochemical determinants of the NP-protein interactions. The objective of this research will be accomplished by pursuing the following specific aims: 1) Develop NP models and their interactions with biomolecules for DMD simulations; 2) Uncover the physicochemical determinants of NP-protein binding; 3) Characterize the structure and dynamics of protein aggregation in the corona; and 4) Extend the research and education in classroom and laboratory more broadly to other education and scientific research community. The developed and validated computational methodology will be shared with the broad scientific research communities. The proposed research projects will uncover the structural and dynamic properties of NP-protein corona at the molecular and atomic level and determine the physicochemical determinants of the molecular complex formation. The obtained results from the proposed mechanistic studies will be pivotal in designing more efficient and safe NPs with optimal properties to promote intended biological functions and minimize the pathological implications of NP exposure. Broader impacts of this proposal include the sustainable development of nanotechnology and improves applications of nanomedicine. Funding of this research will also support students training at the interfaces of physics, material science, biology, and environmental science and engineering, update physics curriculum to reflect the current trend in science, and increase the diversity of physics education and research. The proposed research will develop and validate critical predictive tools to effectively and efficiently model the nano-bio interface, which can be used for engineering NPs with novel biological functions as well as for NP risk assessment. In addition, easy accessibility and enhanced usability of the developed tools will benefit the broad science and engineering community working in the field.