NMR Untersuchungen der Selbstorganisation und Dynamik von amylioden Proteinfibrilen

After synthesis of the unstructured biopolymer chain of amino acids, proteins fold spontaneously into a single, highly ordered, and therefore the biologically active, form. This protein folding reaction is determined by intramolecular interactions within the heteropolymer and the individual 3-dimensional structure is encoded in the sequence of the amino acids. However, another, thermodynamically stable conformation can form, e.g. during pathogenic processes, so called amyloid fibrils. Here, intermolecular interactions between the polymer chains dominate the for­mation of several 100 nm long so-called cross-b structures. The individual 3D structures of different proteins in terms of secondary and tertiary structure differ according to the respec­tive function of the protein. Today, we know the high-resolution structure for more than 50,000 proteins. In contrast, amyloid fibrils formed by different polypeptides show very similar topo­logies rather independent from the individual composition of residues in these biopolymers. More and more evidence accumulates that the amyloid structure represents a generic polymer structure of proteins irrespective of a given amino acid sequence. This strongly suggests that general rather than sequence-specific principles govern fibril formation. The goal of the project is to understand the fundamental physical basis of the fibril formation, which follows very different rules compared to the well studied protein folding code employed by the polypeptide chain to form the biologically active monomeric form. To understand fibril forma­tion, the intermolecular interactions confining the polypeptide conformation inside the fibrils, need to be investigated because they differ from the intramolecular interactions within one monomer. Herein, we want to study the different stages of the self-organization process of amyloid fibrils and the structure and dynamics of the final fibrils by different NMR spectroscopic methods. In particular, we are interested in the questions what physical interactions, what kind of molecular dynamics, and what polymer-specific characteristics influence and stabilize the fibrillar form of a protein in respect to the monomeric chain. This will allow to relate the specific biological question of protein fibril formation to the general and more unifying concepts of polymer aggregation and crystallization to understand the generally inherent properties of amyloid forming proteins, which seem to be generic and not related to the primary amino acid sequence.