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

项目申请：1554508PI: Nguyen， Hung d .动态纳米材料可以改变其形状和结构以响应环境刺激，有望彻底改变医学和生物技术。然而，由于设计空间巨大，缺乏系统的知识和预测模型，目前这种智能材料的发现过程很慢，而且往往是偶然的。事实上，它们的自组装和拆卸过程的定量理解，以及溶液条件和化学结构如何控制它们的形态转变，仍然是难以捉摸的。为了应对这些挑战并充分利用智能材料的潜力，pi将与实验学家合作，通过进行分子模拟，建立一个使用肽-聚合物偶联物的计算机辅助设计集成平台，以促进新型刺激反应纳米材料的快速开发，用于不同的生物医学应用于癌症和基因治疗。拟议的研究将提供及时和宝贵的工具和知识，推动社区加速发现有助于改善生活的智能材料。具体来说，从模拟研究中获得的宝贵见解可能会导致癌症特异性诊断试剂和靶向基因传递系统的发展。提出的CAREER研究计划的具体目标是：1)阐明作为药物或生物显像剂递送载体的peg共轭肽两亲体溶液中的序列-结构-性质关系；2)研究血清和体内条件对肽两亲体刺激反应性自组装的拥挤效应；3)了解肽-聚合物缀合物序列与siRNA复合物结构的关系，以及不同缀合物与siRNA络合的基因传递机制；4)研究siRNA复合物的细胞内运输和肽-聚合物偶联物分解siRNA的机制。通过集成多尺度建模技术，提出的平台将以两种变革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。其次，对序列-结构-性质关系和组装/拆卸过程的集成硅、体外和体内研究将产生新的、系统的知识，这些知识将应用于设计新的刺激反应性运载工具，以改善药物动力学特性。为了扩大计划研究的影响，PI将通过开发生物材料设计的新课程并为本科生提供研究机会，将研究纳入本科课程。此外，PI还将启动一个暑期研究项目，让高中生在他的实验室里进行为期一周的简单模拟，并将在培训初中和高中教师将工程概念和实践经验学习方法融入科学课程方面发挥积极作用。

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.