Mechanism Of Aggregation Dynamics For A? Fragments In Aqueous Solution

Misfolding mechanism of amyloid beta protein(AP)is vital to pathological research of Alzheimer's disease.Hydrophobic sidechain is essential effect to secondary structure,tertiary structure and quaternary structure of protein and play an important role in misfolding aggregation process.The structural dynamics of self-assemble A? segment in solution phase were systematically investigated by modeling various self-assembly fiber model.The research contents are as follows:1.The replica-exchange molecular dynamics were performed for investigation of the structural dynamics of model dipeptides(glycine dipeptide,alanine dipeptide,valine dipeptide,azido-alanine dipeptide)in solution phase,the conformational distributions of model dipeptides with different sidechain in aqueous phase were examined.The dynamical structures of A?37-42 polypeptide and its azido-modification derivatives was systematically investigated for the comprehension of structure distribution of A?37-42.2.Classical molecular dynamic simulations were performed for A?16-21,A?29-34and AP37-42 self-assembled fiber in aqueous solution to observe the aggregation process of nanosheet transform to amyloid fiber.The aggregation machansim of peptide self-assemble was systematically studied by means of transient structure,radial density function(RDFs),MM/PBSA and the Ramachandran Diagram.Discussing principal elements of self-assembled fiber's binding energy.The comprehension of conformation perturbation by introduce azido group into amyloid short fiber was investigated in order to promote the exploitation of amyloid fibril as an emerging class of bionanomaterials.3.Certain C-terminal fragments A?28-42 derived from A?42 were displayed low solubility and high toxicity itself.These short peptide segments A?30-3s and A?35-42 which from parent proteins A?28-42 would form well-ordered fibers.In combination with the results of binding energy decomposition of the A?30-35 and A?35-42 complex fibers and NaOH/NaCl solution effect to A?28-42 fibre,the interaction between the sidechains is not the main factors give risk to A?28-42 self-assembly.The main factor which stabilize A?28-42 fiber should be the salt bridge formed by LYS28 and ALA42.