Temperature-dependent conformational dynamics of cytochrome c: Implications in apoptosis

Heat, electric shock, and burn injuries induce apoptosis by releasing cytochrome c (cyt-c) from mitochondria and by subsequently activating the death protease, caspases-3. During apoptosis, cyt-c undergoes changes in the secondary structure that have been suggested to increase its peroxidase activity. Information about these structural changes will provide better understanding of the apoptotic mechanism. Hence, temperature-dependent conformational dynamics of cyt-c has been investigated through molecular dynamics (MD) simulations to explain the structural changes and to correlate them with its apoptotic behavior. We observe that, at lower temperatures (223, 248, and 300K), the secondary structure of cyt-c, remains stable, while at higher temperatures (323, 373, 423, and 473K), the secondary structural regions change significantly. Further, our MD results indicate that these structural changes are mainly localized on α-helices, turns, β-sheets, and important loops that were involved in the stabilization of the heme conformation. This conformational transition between specific regions of secondary structure of cyt-c directly affects the electron tunneling properties of the proteins as observed experimentally. We quantify and compare these changes and explain that the temperature plays a vital role in assuring the structural stability of cyt-c and thus its functions. Our findings from this MD study reproduce experimental results at high temperatures and provide evidence for the alteration of the heme through the disruption of the H-bonding interactions between specific regions of cyt-c, thereby enhancing its peroxidase activity which plays a crucial role in the apoptotic process.