CAREER: Molecular Recognition and Biological Function at Water-Bilayer Interfaces: Bridging Structure, Dynamics, and Function in Antimicrobial Peptides

太平洋路德大学的Myriam Cotten教授将在国家科学基金会有机和高分子化学项目的职业奖项的支持下，研究两亲性阳离子抗菌肽的结构-功能-动力学关系。两亲性阳离子抗菌肽是一大类活跃于界面的生物分子的重要多肽。长期目标是确定共同原则，以促进设计具有广谱抗菌活性、最低限度诱导细菌耐药性和对哺乳动物细胞低毒的药物。这一研究领域的一个瓶颈是缺乏关于肽-脂相互作用的原子水平信息。Cotten教授的主要目标是在脂质存在的情况下表征选定的抗菌肽的二级结构和动力学。这一知识将被用来确定优化特定分子相互作用的因素，最初是在细胞膜上，这些因素与肽的功能和作用模式直接相关。我们将利用生化、生物物理和光谱学的方法来合成和纯化选定的抗菌肽，并比较它们的原子级结构、分子与脂质的相互作用以及在生理相关条件下的动力学，以促进我们对分子识别、特异性、作用方式和效力的理解。选定的多肽Pissidins将被结合到排列的、水合的脂质双层中，并接受固体核磁共振技术。与生物功能相关的具体参数将被测试。在职业奖项的支持下，对重要抗菌肽的跨学科研究将提供更多的知识，旨在提高我们对这些肽如何识别膜并在不同类型的细胞上启动其活动的基本理解。拟议活动的更广泛影响主要是高质量的科学教育，它将提供给不同的研究小组。这个团队将包括来自代表性不足群体的大学生和预科学生，一名未来的高中教师，以及一名博士后研究员。所有项目参与者都将从事严谨的科学探索和令人愉快的发现。他们将积极促进拟议的研究，前往配备最先进仪器的国家用户设施，并在地方和国家会议上介绍成果。这一计划将有助于激励学生从事专业和个人回报的科学职业，这将有助于科学和劳动力的持续活力。

With the support of a CAREER award from the Organic and Macromolecular Chemistry Program at the National Science Foundation, Professor Myriam Cotten of Pacific Lutheran University will investigate structure-function-dynamics relationships in amphipathic cationic antimicrobial peptides, important peptides belonging to a large family of biomolecules active at interfaces. The long-term goal is to identify common principles that will facilitate the design of pharmaceuticals with broad-spectrum antibacterial activity, minimum induction of bacterial resistance, and low toxicity to mammalian cells. A bottleneck in this area of research is the lack of atomic level information on peptide-lipid interactions. Professor Cotten's main objective is to characterize the secondary structures and dynamics of selected antimicrobial peptides in the presence of lipids. This knowledge will be used to identify factors optimizing specific molecular interactions, initially at cell membranes, that are directly related to peptide function and mode of action. Biochemical, biophysical, and spectroscopic methods will be used to synthesize and purify selected antimicrobial peptides; and to compare their atomic level structures, molecular interactions with lipids, and dynamics under physiologically-relevant conditions to advance our understanding of molecular recognition, specificity, mode of action, and potency. Piscidins, the selected peptides, will be incorporated in aligned, hydrated lipid bilayers and subjected to solid-state nuclear magnetic resonance techniques. Specific parameters relevant to biological function will be tested.With the support of a CAREER award, interdisciplinary research on important antimicrobial peptides will provide results that will feed a larger body of knowledge aimed at improving our fundamental understanding of how these peptides recognize membranes and initiate their activities on different types of cells. Broader impacts of the proposed activity are primarily the high quality science education which will be offered to a diverse research group. This team will include college and pre-college students from underrepresented groups, a future high school teacher, and a postdoctoral fellow. All project participants will engage in rigorous scientific inquiry and delightful discovery. They will actively contribute to the proposed research, travel to national user facilities equipped with state-of-the-art instrumentation, and present results at local and national meetings. This program will help inspire students for professionally and personally rewarding scientific careers that will contribute to continued vitality of the sciences and workforce.