Engineering Protein-based Multifunctional Biomaterials Using Molecular Simulations

预测工具对于加速生物医学应用的材料设计至关重要。分子模拟可以提供材料基本性质的原子分辨率信息，提高我们对结构-功能关系的理解，减少对实验试错的需要。本研究项目以大规模原子模拟和多尺度建模为基础，采用自下而上的方法研究基于蛋白质的多功能生物材料。基于蛋白质的生物材料是生物相容性和可生物降解的替代品，它们的合成对应物。它们可以被精确地设计成显示构象特性，如在结合时折叠，响应环境刺激和自组装。它们的多功能性和生物相容性使它们非常适合广泛的生物医学应用，包括药物和基因输送。这项研究计划的长期目标是设计基于蛋白质和多肽的多功能基因传递系统。我们将利用分子模拟的力量，为合理的生物材料设计提供系统的方法。将与试验组建立合作，以在体外和体内测试铅输送系统的功效。在短期内，将进行以下研究：(i)设计生物相容性和可生物降解的基于蛋白质的纳米笼作为siRNA递送系统；（ii）设计能够逃离核内体的肽融合基因传递系统；（iii）阐明配体-受体相互作用的动力学，以更好地设计主动靶向策略。拟议的研究将为在生物材料设计中使用计算技术建立一个框架，并有助于开发无毒的靶向基因传递系统。在更基本的层面上，从研究蛋白质和多肽作为生物材料中获得的方法学见解将为基因传递系统的开发提供严格的设计策略和预测工具。该研究成果将有助于加拿大生物医学部门设计用于癌症治疗的下一代生物材料。

Predictive tools are crucial to accelerate material design for biomedical applications. Molecular simulations can provide atomic-resolution information on the fundamental properties of materials, bettering our understanding of the structure - function relationships and reducing the need for experimental trial and error. This research program focusses on engineering multifunctional protein-based biomaterials with a bottom-up approach, using large scale atomistic simulations and multiscale modeling. Protein-based biomaterials are biocompatible and biodegradable alternatives to their synthetic counterparts. They can be precisely engineered to display conformational properties such as folding upon binding, respond to environmental stimuli, and self-assemble. Their versatility and biocompatibility make them well-suited for a wide range of biomedical applications including drug and gene delivery. The long-term objective of this research program is to engineer protein and peptide-based, multifunctional gene delivery systems. We will harness the power of molecular simulations to provide a systematic approach to rational biomaterial design. Collaborations with experimental groups will be established to test the efficacy of the lead delivery systems in vitro and in vivo. In the short term, studies will be conducted to: (i) engineer biocompatible and biodegradable protein-based nanocages as siRNA delivery systems; (ii) design peptide fusion gene delivery systems capable of escaping endosomes; (iii) elucidate the dynamics of ligand-receptor interactions to better design active targeting strategies. The proposed studies will establish a framework for the use of computational techniques in biomaterial design and help develop non-toxic, targeted gene delivery systems. On a more fundamental level, the methodological insights gained from studying proteins and peptides as biomaterials will provide rigorous design strategies and predictive tools in the development of gene delivery systems. The research outcomes will help Canadian biomedical sector to engineer next generation biomaterials for cancer treatment.