Structure, self-assembly properties and mechanism of action of antimicrobial peptides, amyloid peptides and silk proteins

我们的研究重点是几种生物医学感兴趣的多肽和蛋白质的结构、自组装特性和作用机制的确定。我们将专注于抗生素耐药性和依赖于多肽/蛋白质的结构和组装的神经退行性疾病。我们还将研究天然和人工合成蚕丝的生产，以帮助开发生物材料，特别是用于组织再生的植入物和支架。这些系统将通过结合新的固态核磁共振方法进行研究，并将通过其他几种生物物理技术获得补充信息。 多重耐药细菌的急剧增加导致了寻找新的治疗方法的相当大的努力。因此，必须设计具有新作用模式的新抗生素来对抗微生物感染，而抗菌肽是很有希望的候选药物。将研究人工合成的两亲性多肽的结构和膜相互作用。更具体地说，我们将研究赖氨酸取代肽和精氨酸取代肽的结构、膜拓扑结构和齐聚作用。 比较天然抗菌肽和合成抗菌肽的作用模式是非常有意义的。我们将研究一种天然抗菌肽--抗菌素与模拟真核和原核细胞的脂膜之间的相互作用。由于Thanatin在体内诱导细菌凝集，不同组成的单层脂泡的聚集以及多肽的二级结构和膜相互作用都会随之发生。 淀粉样变性是指一系列退行性疾病，包括阿尔茨海默病和帕金森病，表现为淀粉样蛋白在组织上沉积，原因是蛋白质异常自组装并沉积到称为淀粉样纤维的不溶性聚集体中。我们建议研究两个与膜相关的淀粉样多肽的结构和自组装特性，即与帕金森病相关的α-突触核蛋白片段和与不同淀粉样变性相关的转甲状腺蛋白片段。 蜘蛛丝是指由纤维蛋白组成的一系列生物材料，它们以分级的方式自组装，产生各种具有特殊机械性能和潜在应用的纤维，如组织工程中的缝合、韧带和肌腱。我们将研究重组丝蛋白在溶液中的结构、热稳定性和聚集动力学。鞭毛状丝绸的纤维也将被研究，这种纤维形成了球状网的捕获螺旋。我们还将确定丝蛋白在溶液和纳米晶中的C-末端结构域。

Our research program focuses on the determination of the structure, self-assembly properties and mechanism of action of several peptides and proteins of biomedical interest. We will focus on antibiotic resistance and neurodegenerative diseases that rely on the structure and assembly of peptides/proteins. We will also study the natural and synthetic production of silk to help in developing biomaterials, especially implants and scaffolds for tissue regeneration. These systems will be investigated by a combination of novel solid-state nuclear magnetic resonance approaches and complementary information will be obtained by several other biophysical techniques. The dramatic increase in multi-drug-resistant bacteria has led to considerable efforts to find new therapeutic approaches. The design of new antibiotics with novel modes of action is therefore mandatory to fight against microbial infections and antimicrobial peptides are promising candidates. The structure and membrane interactions of synthetic amphipathic peptides will be investigated. More specifically, we will investigate the structure, membrane topology and oligomerization of both lysine-substituted and arginine-substituted peptides. Comparing the mode of action of natural vs. synthetic antimicrobial peptides is of great interest. We will investigate the interaction of a natural antimicrobial peptide, thanatin, with lipid membranes that model eukaryotic and prokaryotic cells. Since thanatin induces the agglutination of bacteria in vivo, the aggregation of unilamellar lipid vesicles of different compositions will be followed, as well as the secondary structure of the peptide and its membrane interactions. Amyloidosis refers to a family of degenerative diseases, including Alzheimer’s and Parkinson’s diseases, which demonstrate amyloid protein deposits on tissues resulting from the abnormal self-assembly and deposition of proteins into insoluble aggregates known as amyloid fibrils. We propose to investigate the structure and self-assembly properties of two amyloid peptides in solution and associated with membranes, namely a fragment of the protein a-synuclein involved in Parkinson’s disease and a fragment of the protein transthyretin involved in different amyloidoses. Spider silk refers to a range of biological materials made of fibrous proteins that self-assemble in a hierarchical manner to produce various fibers with exceptional mechanical properties and promising applications such as stitches, ligaments and tendons from tissue engineering. We will investigate the structure, thermal stability and aggregation kinetics of recombinant silk proteins in solution. Fibers of flagelliform silk, which forms the capture spiral of orb webs, will also be investigated. We will also determine the structure of the C-terminal domain of silk proteins both in solution and as nanocrystals.