Browsing by Author "Mohajer, Faeze Sadat"

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    Effects of acta-1 mutations on actin-myosin interaction using molecular dynamics
    (Universiti Teknologi Malaysia, 2018) Mohajer, Faeze Sadat
    Recently, over 170 mutations on the actin accumulation myopathy protein (ACTA-1) have been found to be related to congenital myopathies with five of which are located on the actin-myosin interface; S350L, G48C/D and E336A/K; and the molecular mechanism of these mutations has yet to be elucidated. This limited understanding impedes deployment of potential treatment regimen to counter the catastrophic symptoms of this disease. This study was aimed to elucidate the effects on these mutations on the structures of the actin, actin-myosin interactions, actin-actin binding proteins interactions, as well as the stability or overall structure of F-actins, with the use of in-silico methods. The 3D structure of the proteins was constructed by comparative modelling techniques, mutated and then finally simulated with a molecular dynamics simulation for a proper analysis on the structural impact of the mutations. Furthermore, the effects of the mutations on the actin-myosin interface were also analysed. Finally, the effects of mutations on the interaction of actin with its peripheral proteins and structure or stability of the F-actins were analysed. The results demonstrated that the S350L leads to the formation of an additional a-helix in actin in S352-M357, a reduction in surface area, and an increase in the hydrophobicity of both outer layers of F-actins, causing the failure of a-actinine and nebulin to properly become attached to actin. As a consequence, this prohibits F-actins from being thoroughly arranged and assembled in the horizontal axis, which leads to F-actins accumulation. L350 was unable to interact with myosin, since it lacks a hydroxyl group. G48C/D changes the structural alignment of the D-loop and prevent the D-loop from properly wrapping around Y171 of the adjacent G-actin. This phenomenon causes the rise of congenital fibre type disproportion symptoms. C48/D48 are unable to form hydrogen bond (H-bond) with myosin, since they are located far away from this protein. E336A/K caused the increased distance and consequential loss of hydrogen bond formations between residue 336 and S147, due to the absence of the acidic group in Ala and Lys with weakened interaction between actin and myosin. These mutations also affect the electrostatic interaction between K644 of myosin and E336 of actin, further weakening the actin-myosin interaction. In conclusion, the disease is caused by a small defect in the actin structure that is amplified by the repetitive design of muscle fibres, which comprises defective sarcomeres. The locations of the mutations are shown to be more crucial compared to the type of amino acid substituted. The effect of a single H-bond or electrostatic interaction loss is amplified by the repetitive nature of G-actins in the structure of F-actin throughout the muscular structure. Therefore, even loss of one of the H-bonds or electrostatic interactions between myosins and actins would cause systemic muscular contraction weakness. The elucidation of this phenomenon will increase understanding of role the actin-myosin actin role in congenital myopathies