Multi-Target Design and Analysis of DNA-Binding Antimicrobial Peptides

抗微生物肽（AMP）是一种潜在的有前途的策略， 持续的健康危机的抗药性微生物感染，因为他们的目标 通用细菌结构元件，从而呈现进化途径， 细菌耐药性更难。一些AMP具有一种假设的机制， 首先涉及与细菌细胞膜相互作用并易位的作用 穿过它进入细菌细胞一旦这些抗菌肽进入细菌， 与细胞内靶点如DNA结合。这些阳离子肽和 它们的带负电荷的膜和核酸靶都介导 很大程度上是由于静电。 该项目涉及抗菌肽的设计与增加抗菌效力 通过合理修饰五种被认为靶向核酸的AMP， 增强的膜和DNA结合亲和力。项目工作流集成了 计算技术，如优化，分子动力学模拟， 用实验技术，如光谱学， 微生物测试和基于囊泡的测定。这种多方面的方法将使 不仅是为了开发更有活性的治疗方法， 了解静电驱动系统中的多目标分子识别。 具体而言，研究团队将首先设计具有一系列亲和力的肽 每一个单一的目标-无论是膜或DNA -其次是研究，以确定如何 结合亲和力涉及抗微生物效力和作用机制。基于 根据这些结果，他们将设计和分析共同优化的肽， 对膜和DNA靶标混杂。通过比较 由于不同的目标而产生的设计，研究团队将深入了解 分子识别的机制。该项目还将提供丰富的 计算和实验的循环，可用于改善基于物理的 模型，并产生一个设计框架，可应用于其他肽系统。 除了这些科学目标外，这项工作还将侧重于加强教育， 以及在韦尔斯利学院的培训机会， 机构。通过这项研究，韦尔斯利的学生将有机会采取 在计算和实验的接口项目的所有权。

Antimicrobial peptides (AMPs) are a potentially promising strategy to address the ongoing health crisis of antibiotic-resistant microbial infection because they target generic bacterial structural elements, thereby rendering evolutionary pathways for bacterial resistance more difficult. Some AMPs have a hypothesized mechanism of action that first involves interacting with the bacterial cell membrane and translocating across it to enter the bacterial cell. Once these AMPs enter bacteria, they can interact with intracellular targets such as DNA. Interactions between these cationic peptides and both of their negatively-charged membrane and nucleic acid targets are mediated in large part by electrostatics. This project involves the design of AMPs with increased antimicrobial potency through rationally modifying five AMPs believed to target nucleic acids to achieve enhanced membrane and DNA binding affinity. The project workflow integrates computational techniques, such as optimization, molecular dynamics simulations, and continuum electrostatic modeling with experimental techniques, such as spectroscopy, microbiological testing, and vesicle-based assays. This multifaceted approach will allow for not only the engineering of potentially more active therapeutics but also the deeper understanding of multi-target molecular recognition in electrostatically-driven systems. Specifically, the research team will first design peptides with a range of affinities to each single target – either membrane or DNA – followed by studies to determine how binding affinity relates to antimicrobial potency and mechanism of action. Based on these results, they will then design and analyze peptides co-optimized to ideally interact promiscuously to both membrane and DNA targets. By comparing structural bases of designs resulting from different objectives, the research team will gain insight into the mechanisms of molecular recognition in this system. The project will also provide a rich cycle of computation and experiment that can be used to improve physically-based models and yield a design framework that can be applied to other peptide systems. In addition to these scientific goals, this work will focus on enhancing educational and training opportunities at Wellesley College, a women’s undergraduate-only institution. Through this research, Wellesley students will have the opportunity to take ownership of projects at the interface of computation and experiment.