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

随着纳米技术的快速发展，工程纳米颗粒（NPs）可能有意或无意地释放到环境和生物系统中。以环境和生物介质中富集的许多蛋白质为功能基石，它们可以被吸收到NP表面，形成所谓的NP蛋白冠。细胞和组织“看到”的是蛋白质冠状体，而不是原始的NPs，并随后决定这些释放的NPs的生物学和/或病理功能。本提案的目的是开发和应用最先进的计算机模拟方法，以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NP的设计，以促进预期的生物学功能并防止意外的病理反应，使“设计安全”成为广泛的科学和工程界建模和预测冠状病毒形成以及NP暴露的快速风险评估。在这个CAREER提案中，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。本研究将通过以下具体目标来实现：1)建立用于DMD模拟的NP模型及其与生物分子的相互作用；2)揭示np蛋白结合的理化决定因素；3)表征冠状病毒中蛋白质聚集的结构和动力学；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研领域。开发和验证的计算方法将与广泛的科学研究界共享。拟建的研究项目将在分子和原子水平上揭示np -蛋白冠的结构和动态特性，并确定分子复合体形成的物理化学决定因素。从机制研究中获得的结果将是设计更有效、更安全、具有最佳特性的NP的关键，以促进预期的生物学功能，并最大限度地减少NP暴露的病理影响。这项提议的更广泛的影响包括纳米技术的可持续发展和改进纳米医学的应用。这项研究的资金还将支持学生在物理学、材料科学、生物学、环境科学和工程等领域的培训，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。该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，这可以用于具有新型生物功能的工程NPs以及NP风险评估。此外，开发的工具易于访问和增强的可用性将使在该领域工作的广泛的科学和工程社区受益。

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.