Bioorganic Methodology to Create Novel Biomolecular Platforms to Address Critical Needs in Molecular Recognition and Function

生物有机方法论创建新型生物分子平台，以满足分子识别和功能的关键需求

• 批准号: RGPIN-2017-05232
• 负责人: Honek, John
• 金额: $ 4.37万
• 依托单位: University of Waterloo
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=711468
• 关键词: Bioorganic; Methodology; Create; Novel; Biomolecular

This research program focuses on the creation of novel biomolecular scaffolds that will become key elements in the chemical design of selective affinity receptors for small organic and inorganic molecules as well as unique molecular frameworks useful in controlling macromolecule interactions with chemical surfaces and advanced materials. The creation of innovative molecular recognition systems is a critical enabling technology that underpins the development of new materials and therapeutic agents for society. Chemical and biochemical manipulation of complex multisubunit proteins and viruses will be undertaken to serve as unique, self-assembling biomolecular platforms valuable for materials and biomaterials science. Currently intense interest is being directed toward the application of large multisubunit proteins and viruses to the synthesis of molecular scaffolds able to "hang and orient" photovoltaic systems, or to serve as building blocks for the fabrication of biomolecular batteries, novel biofibers or drug delivery systems. Hence there is exceptional need for developing the chemistry of these complex structures and to train the next generation of scientists to contribute to the application of renewable biosystems to materials science, energy systems and therapeutics. Various levels of biomolecular complexity will be explored by these chemical approaches. These include: A) Chemical manipulation and protein engineering of cavity-containing multisubunit spherical proteins which range in complexity (24 to 180 protein subunits), mass (440 kDa to 6.9 MDa) and diameter (120-320 ). Our research program in this area is to develop new ways to control their inner and outer molecular surfaces as well as to develop approaches to create new host-guest macromolecular complexes using engineered protein components. B) Development of bioorganic approaches to create novel "virus-based molecular platforms" (linear bacteriophage M13, ~ 2770 protein subunits, ~ 60 in diameter and ~ 1 micron in length; mass 16.8 MDa) to serve as unique biomolecular scaffolds potentially useful in materials and (bio)materials science. We have successfully utilized a bioorganic approach to incorporate unnatural amino acids into the major sheath protein of M13 and, in one example, displayed > 350 azide moieties on the M13 surface which were further chemically modified to controllably attach fluorescent dyes and gold nanoparticles. Research to explore the additional capabilities of this engineered bacteriophage will be continued. For example, the ability to place recognition peptides onto the “ends” of these bacteriophage scaffolds and to furthermore crosslink them into larger complexes, should allow for the molecular delivery and/or targeting of these megabiocomplexes to a variety of materials and surfaces.

这项研究计划专注于创造新型生物分子支架，这些支架将成为有机和无机小分子选择性亲和力受体化学设计的关键元素，以及用于控制大分子与化学表面和先进材料相互作用的独特分子框架。创新的分子识别系统的创建是一项关键的使能技术，它为社会开发新材料和治疗剂奠定了基础。复杂的多亚单位蛋白质和病毒的化学和生化操作将成为对材料和生物材料科学有价值的独特的、自组装的生物分子平台。目前，人们对大分子多亚单位蛋白质和病毒在合成分子支架方面的应用产生了浓厚的兴趣，这些分子支架能够“悬挂和定向”光伏系统，或者用作制造生物分子电池、新型生物纤维或药物输送系统的积木。因此，特别需要发展这些复杂结构的化学，并培训下一代科学家，以促进可再生生物系统在材料科学、能源系统和治疗方面的应用。这些化学方法将探索不同水平的生物分子复杂性。这些措施包括： A)含有空腔的多亚基球形蛋白质的化学操作和蛋白质工程，其复杂性(24至180个蛋白质亚基)、质量(440 kDa至6.9 mda)和直径(120至320)不等。我们在这一领域的研究计划是开发新的方法来控制它们的内外分子表面，以及开发利用工程蛋白质组分创建新的主客体大分子复合体的方法。 B)开发生物有机方法以创建新的“基于病毒的分子平台”(线性噬菌体M13，~2770个蛋白质亚基，直径~60个，长度~1微米；质量16.8丙二醛)，作为独特的生物分子支架，在材料和(生物)材料科学中具有潜在的应用价值。我们成功地利用生物有机方法将非天然氨基酸整合到M13的主要鞘蛋白中，在一个例子中，在M13表面展示了&gt；350叠氮部分，这些部分经过进一步的化学修饰，可控制地附着荧光染料和金纳米颗粒。探索这种工程噬菌体的额外能力的研究将继续进行。例如，将识别肽放置在这些噬菌体支架的“末端”上并进一步将它们交联成更大的复合体的能力，应该允许这些巨型复合体的分子输送和/或靶向各种材料和表面。