CAREER: Fundamental Understanding of Self-Assembly by Peptide-Polymer Conjugates in Creating Functional Biomaterials from Multiscale Simulations

建议：1554508 PI：Nguyen，Hung D.动态纳米材料可以根据环境刺激改变其形状和结构，有望彻底改变医学和生物技术。然而，目前这种智能材料的发现过程是缓慢的，而且由于设计空间巨大，缺乏系统的知识和预测模型，往往是偶然的。事实上，他们的自我组装和拆卸过程的定量理解，以及如何解决的条件和化学结构管理其形态转变，仍然难以捉摸。为了应对这些挑战并充分利用智能材料的潜力，PI将通过与实验学家合作进行分子模拟，建立一个使用肽-聚合物缀合物的计算机辅助设计的综合平台，以促进快速开发新型刺激响应纳米材料，用于癌症和基因治疗的不同生物医学应用。拟议的研究将提供及时和宝贵的工具和知识，推动社区加快发现有助于改善生活的智能材料。CAREER研究计划的具体目标是：1）阐明溶液中的序列-结构-性质关系，用于从头设计PEG结合的肽两亲物作为药物或生物成像剂的载体; 2）研究血清和体内条件对肽两亲物刺激响应性自组装的拥挤效应：3）了解肽-聚合物缀合物序列与siRNA复合物结构之间的关系以及不同缀合物与siRNA复合用于基因递送的机制; 4）研究siRNA复合物的胞内运输和siRNA通过肽-聚合物缀合物分解的机制。通过整合多尺度建模技术，该平台将以两种变革性的方式创新和加速材料发现过程。首先，新模型和模拟工具的发展将推动多尺度建模的边界，并为新型生物材料的计算机辅助设计铺平道路。第二，整合的序列-结构-性质关系和组装/拆卸过程的计算机模拟和体外和体内研究将产生新的、系统的知识，这些知识将被应用于设计新的刺激响应性递送载体，以改善药效动力学性质。为了扩大计划研究的影响，PI将通过开发生物材料设计新课程并为本科生提供研究机会，将研究融入本科课程。此外，PI还将为高中生推出一项夏季研究计划，让他们在实验室进行为期一周的简单模拟，并将在培训初中和高中教师方面发挥积极作用，将工程概念和实践体验式学习方法融入他们的科学课程。

Proposal: 1554508PI: Nguyen, Hung D.Dynamic nanomaterials that can change their shape and structure in response to environmental stimuli hold promise to revolutionize medicine and biotechnology. However, the current discovery process of such smart materials is slow and often serendipitous due to the enormously large design space and lack of systematic knowledge as well as predictive models. Indeed, a quantitative understanding of their self-assembly and disassembly processes, and how the solution condition and chemical structure govern their morphological transition, has remained elusive. To tackle these challenges and harness the full potential of smart materials, the PIs will build an integrated platform of computer-aided design using peptide-polymer conjugates by performing molecular simulations in collaboration with experimentalists in facilitating rapid development of novel stimuli-responsive nanomaterials for different biomedical applications in cancer and gene therapy. The proposed research will provide timely and invaluable tools and knowledge to move the community towards expedited discovery of smart materials that help improve lives. Specifically, the valuable insights gained from the simulation studies could lead to the development of a cancer-specific diagnostic agent and targeted gene delivery system.The specific objectives of the proposed CAREER research program are: 1) elucidate the sequence-structure-property relationships in solution for de novo design of PEG-conjugated peptide amphiphiles as delivery vehicles of drugs or bioimaging agents; 2) examine the crowding effects of the blood serum and in vivo conditions on stimuli-responsive self-assembly by peptide amphiphiles; 3) understand the relationship between peptide-polymer conjugate sequence and structure of siRNA complexes and mechanisms of siRNA complexation by different conjugates for gene delivery; and 4) investigate the mechanisms of intracellular trafficking of siRNA complexes and siRNA disassembly by peptide-polymer conjugates. By integrating multi-scale modeling techniques, the proposed platform will innovate and accelerate the materials discovery process in two transformative ways. First, the development of new models and simulations tools will push the boundary of multi-scale modeling and pave the way for computer-aided design of novel biomaterials. Second, the integrated in silico and in vitro and in vivo studies of sequence-structure-properties relationships and assembly/disassembly processes will generate novel, systematic knowledge that will be applied to design novel stimuli-responsive delivery vehicles for improved pharmaco-kinetic properties. To broaden the impact of the planned research, the PI will integrate research into the undergraduate curricula by developing a new course on biomaterial design and offering research opportunities for undergraduate students. Furthermore, the PI will launch a summer research program for high school students to perform simple simulations in his laboratory for one week and will play an active role in training middle and high school teachers to integrate engineering concepts and hands-on experiential learning methodologies into their science curriculum.