A molecular journey to check the conformational dynamics of tau tubulin kinase 2 mutations associated with Alzheimer's disease

Abstract

Proteins are one of the most vital components of biological functions. Proteins have evolutionarily conserved structures as the shape and folding pattern predominantly determine their function. Considerable research efforts have been made to study the protein folding mechanism. The misfolding of protein intermediates of large groups form polymers with unwanted aggregates that may initiate various diseases. Amongst the diseases caused by misfolding of proteins, Alzheimer's disease (AD) is one of the most prevalent neuro-disorders which has a worldwide impact on human health. The disease is associated with several vital proteins and single amino acid mutations. Tau tubulin kinase 2 (TTBK2) is one of the kinases which is known to phosphorylate tau and tubulin. The literature strongly supports that the mutations-K50E, D163A, R181E, A184E and K143E are associated with multiple important cellular processes of TTBK2. In this study, to understand the molecular basis of the functional effects of the mutations, we have performed structural modeling for TTBK2 and its mutations, using computational prediction algorithms and Molecular Dynamics (MD) simulations. The MD simulations highlighted the impact of the mutations on the Wild Type (WT) by the conformational dynamics, Free Energy Landscape (FEL) and internal molecular motions, indicating the structural de-stabilization which may lead to the disruption of its biological functions. The destabilizing effect of TTBK2 upon mutations provided valuable information about individuals carrying this mutant which could be used as a diagnostic marker in AD.