Molecular dynamics simulation approach to explore atomistic molecular mechanism of peroxidase activity of apoptotic cytochrome c mutants

摘要

Mutations in cytochromec(Cytc) have been reported in tuning peroxidase activity, which in-turn cause Cytcrelease from mitochondria and early apoptosis. However, the molecular tuning mechanism underlying this activity remains elusive. Herein, multiple 20 ns molecular dynamics (MD) simulations of wild type (WT), Y67F and K72W mutated Cytcin aqueous solutions have been carried out to study how the changes in structural features alters the peroxidase activity of the protein. MD simulation results indicate that Y67F mutation caused, (i) increased distances between critical electron-transfer residues, (ii) higher fluctuations in omega loops, and (iii) weakening of intraprotein hydrogen bonds result in open conformation at heme crevice loop in Cytcleading to an enhanced peroxidase activity. Interestingly, the aforementioned structural features are strengthened in K72W compared to WT and Y67F, which triggers K72W mutated Cytcinto a poor peroxidase. Essential dynamics results unveil that first two eigenvectors are responsible for overall motions of WT, Y67F and K72W mutated Cytc. This study thus provides atomic level insight into molecular mechanism of peroxidase activity of Cytc, which will help in designing novel Cytcstructures that is more desirable than natural Cytcfor biomedical and industrial processes.