Abstract :

Exploring the nature of protein folding, the following work is an elucidation of a bio-mathematical explanation of the Levinthals paradox using Clustering Partition among different torsional states in conjunction with Random Walk Theory. The kinetics of protein folding mechanisms have been resolved by integrating Overlapping Clusters across different Hierarchical Levels of protein folding, from simplest (Primary) to the most folded (Tertiary) structural conformations by introducing stochastic perturbations. The analytical dynamics of attaining stable conformations and at the same time spontaneous loss of native structures pave the way to protein misfolding and the self-propagating phenomenon of toxic protein intermediates in neurodegenerative diseases. The pathophysiological manifestations of one such protein Amyloid-beta, implicated in Alzheimers disease-meandering through states of the beta-amyloid fibril accumulation, has been addressed; along with an investigation into the tau proteins instability and related clinical conditions upon exposure to metal ion induced neurotoxicity. The two major hypotheses of Alzheimers Disease: the Amyloid Cascade Theory followed by the Microbial Infection Theory have been scrutinized and unified on the basis of their convergence to genetic dysbiosis; associating unusual interactions among proteins as well as head towards the existence of a probable link between the protein modifications and microbe induced protein misfolds. This has been followed by an investigation into the dynamics of Amyloid fibril propagation, in a model analogous to Prion replication. The immense coverage of this bio-mathematical study can help decipher the complex molecular mechanisms underlying the process of protein folding and help supplement clinical investigations into the causes and remedies of Alzheimers disease.