Molecular dynamics simulations to explain potential mechanism of mitochrondria outer membrane permeabilization
I am interested in how the micro-scale events, driven by fundamental chemical and physical properties, are connected to biological phenomena. These dynamic events span six or more orders of magnitude in space and time from the atomic detailed level to the cellular or organism level. In particular, I am interested in understanding apoptosis or programmed cell death (PCD). Deregulated PCD has been shown to occur in neurodegenerative disease, bone marrow failure, and is a hallmark of cancer. The goal of my research is to understand the molecular interactions among apoptosis activators, sensitizers, effectors and inhibitors that drive mitochondria outer membrane permeabilization (MOMP). MOMP is considered the commitment step in the mitochondrial apoptosis execution and it is tightly regulated interactions among the Bcl-2 family of proteins. The consensus mechanism for MOMP involves the oligomerization of Bax proteins into structures that enable permebealiziation. This oligomerization is coupled with activation by Bid and inhibition by Bcl-xL. However, the molecular-level detail associated with these interactions are challenging to elucidate experimentally and much needed to achieve a predictive understanding of MOMP dynamics. In this my work, I employ atomistic molecular dynamics simulations to explore the stability of Bax oligomers in pore conformations. We further explore the contributions of membrane composition to oligomer localization, stability, and permabilization. We also show our preliminary results using free energy calculation methods to estimate reaction rates between Bid, Bax, and Bcl-xL. This will help us explain potential mechanisms for MOMP and contribute toward a consensus model of PCD execution.