Amyloid Evolution: Antiparallel Replaced by Parallel

in Biophysical Journal (2020), 118

Several atomic structures have now been found for micrometer-scale amyloid fibrils or elongated microcrystals using a range of methods, including NMR, electron microscopy, and X-ray crystallography, with ... [more ▼]

Several atomic structures have now been found for micrometer-scale amyloid fibrils or elongated microcrystals using a range of methods, including NMR, electron microscopy, and X-ray crystallography, with parallel beta-sheet appearing as the most common secondary structure. The etiology of amyloid disease, however, indicates nanometer-scale assemblies of only tens of peptides as significant agents of cytotoxicity and contagion. By combining solution X-ray with molecular dynamics, weshow that antiparallel structure dominates at the first stages of aggregation for a specific set of peptides, being replaced by parallel at large length scales only. This divergence in structure between small and large amyloid aggregates should inform future design of molecular therapeutics against nucleation or intercellular transmission of amyloid. Calculations and an overview from the literature argue that antiparallel order should be the first appearance of structure in many or most amyloid aggregation processes, regardless of the endpoint. Exceptions to this finding should exist, depending inevitably on the sequence and on solution conditions. [less ▲]

Thermodynamics and Aggregation Kinetics of Lysozyme-Derived Peptides

Doctoral thesis (2019)

When multiple similar protein or peptide chains form non-covalent aggregates, this is termed 'amyloid'. Many serious progressive diseases such as Alzheimer's and Parkinson's are related to undesirable ... [more ▼]

When multiple similar protein or peptide chains form non-covalent aggregates, this is termed 'amyloid'. Many serious progressive diseases such as Alzheimer's and Parkinson's are related to undesirable amyloid aggregation. From a positive perspective, functional amyloids have applications as robust and versatile biomaterials in nature, nanotechnology, and biomedicine. To probe the properties of the amyloid aggregation process in terms of the structure of molecules and the microscopic interactions between them, molecular simulation methods such as molecular dynamics (MD) and Monte Carlo (MC) can be used. These tools are especially valuable to illustrate short length and time scales not easily accessible for systems in solution via current experimental techniques. In this work the thermodynamics and aggregation kinetics of the ILQINS hexapeptide are studied. ILQINS is a biological material derived from hen's egg-white lysozyme. Two ILQINS homologues, IFQINS and TFQINS are compared to ILQINS and some of the complex physics which leads to the increased amyloidogenicity of these species, which is not expected from first-order consideration of amino acid properties, is discussed. The IFQINS hexapeptide is of particular interest as the human homologue of ILQINS. Solution X-ray and X-ray crystallography are compared to simulation, verifying that at least two metastable polymorphic structures exist for this system which are substantially different at the atomistic scale, and illustrating the physics driving kinetic competition between polymorphs. [less ▲]