How cytochrome C is released from the mitochondria to the cytosol via Bax oligomeric pores, a process which is required for apoptosis, is still a mystery. Based on the residue-residue distances detected experimentally for Bax and its homologous protein (Bak), we recently computationally solve the first atomic model for Bax oligomeric pores at the membranes. Next, we investigate the mechanism at the microsecond time- and nanometer space- scale using coarse-grained replica exchange and all-atom MD simulations. Our free energy landscape depicts a low barrier for the permeation of cytochrome C into the Bax C-terminal mouth, with the pathway proceeding to the inner cavity and exiting via the N-terminal mouth. Release is guided by organized charged/hydrophilic surfaces. The hydrophilicity and negative charge of the pore surface gradually increase along the release pathway from the pore entry to the exit opening. Rather than inert passing of cytochrome C through a rigid pore, the flexible pore may selectively aid the cytochrome C passage. The energy barrier is under 4 kcal/mol. Thus, once the Bax pore is formed in the membrane, the release of cytochrome C may be readily achieved through energy fluctuations. Collectively, our work provides mechanistic insight and atomic detail into the release of cytochrome C through Bax oligomeric pores.

Citation Format: Mingzhen Zhang, Jie Zheng, Ruth Nussinov, Buyong Ma. Molecular dynamics simulation of permeation pathway of cytochrome C through Bax pore [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2310. doi:10.1158/1538-7445.AM2017-2310