FET: Small: Simulation-guided design of heterochiral DNA nanostructures for biomaterials applications

DNA纳米技术旨在利用DNA作为支架材料，在分子尺度上组装具有纳米精度的工程化结构。虽然大多数DNA纳米技术分子利用的是自然产生的右旋形式的DNA，即D-DNA，但另一种选择是使用化学合成的“左撇子”DNA，即L-DNA，从而能够创造出反向扭曲的DNA物体。L脱氧核糖核酸分子的一个实际优势是，它们可以抵抗生物环境中酶的降解，生物环境中的酶已经进化到能够识别D-脱氧核糖核酸。另一方面，虽然D-DNA分子更容易降解，但它们可以直接与DNA和RNA等生物核酸对接。因此，将这两种形式的DNA结合成单一的手性杂化或异手性DNA形式可能是有利的。该项目将通过研究这种异手性纳米结构的结构和功能，并利用这些知识来设计新型的功能DNA纳米设备，从而促进DNA纳米技术的发展。计算模型和实验结果将向更广泛的研究界传播，该项目将培训研究生和本科生，包括那些来自代表性不足群体的学生，掌握跨学科研究技能。公众推广工作将与当地伙伴机构合作进行。在分子水平上，异手性DNA连接可能会对较大的DNA纳米技术对象的稳定性和结构产生重大影响。本项目将使用分子动力学模拟来研究异手性DNA双螺旋在手性交叉区域的结构，由于这些分子的新颖性，目前对这些分子的结构了解很少。这些模拟的结果将被用来预测异手性DNA的行为，这将得到实验验证。该项目将制定结合D-DNA和L-DNA成分的DNA纳米结构的工程设计规则，其广泛目标是控制这些纳米结构在生物环境中的降解路径。这将通过研究这些成分在模拟体内条件的模型生物流体中的行为来得到验证。所获得的结果将增强关于DNA不同手性之间相互作用的DNA结构的知识，并将引导异手性DNA作为生物医学应用的功能生物材料的实际应用。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

DNA nanotechnology aims to use DNA as a scaffolding material to assemble engineered structures at the molecular scale, with nanometer precision. While most DNA nanotechnology molecules make use of DNA in the naturally occurring right-handed form known as D-DNA, an alternative uses chemically synthesized “left-handed” DNA, known as L-DNA, enabling the creation of DNA objects that twist in the opposite direction. A practical advantage of L-DNA molecules is that they resist degradation by enzymes in biological environments, which have evolved to recognize D-DNA specifically. On the other hand, while D-DNA molecules are more prone to degradation, they can interface directly with biological nucleic acids such as DNA and RNA. Therefore, it may be advantageous to combine the two forms of DNA into a single chiral hybrid, or “heterochiral”, form of DNA. This project will contribute to advancing the state of the art in DNA nanotechnology by studying the structure and function of such heterochiral nanostructures and by using this knowledge to engineer novel functional DNA nanodevices. Computational models and experimental results will be disseminated to the broader research community, and this project will train graduate and undergraduate students, including those from underrepresented groups, in interdisciplinary research skills. Public outreach efforts will be carried out in conjunction with local partner institutions.At the molecular level, a heterochiral DNA junction may have drastic effects on the stability and structure of a larger DNA nanotechnology object. This project will use molecular dynamics simulations to study the structures of heterochiral DNA double helices in the region of a chiral crossover, currently a poorly understood aspect of DNA structure given the novelty of these molecules. The results of these simulations will be used to make predictions about the behavior of heterochiral DNA, which will be validated experimentally. The project will produce engineering design rules for DNA nanostructures that combine D-DNA and L-DNA components, with the broad goal of controlling degradation pathways for these nanostructures in biological environments. These will be verified by studying the behavior of these components in model biological fluids that mimic conditions in vivo. The results obtained will enhance knowledge of DNA structure with regard to the interactions between different chiralities of DNA and will lead the way to practical applications of heterochiral DNA as a functional biomaterial for biomedical applications.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.