Molecular Mechanisms of Lipid and Ion Translocation in a Phospholipid Scrambling Machinery

Tao Jiang, University of Illinois at Urbana-Champaign

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Emad Tajkhorshid, Po-Chao Wen, Tao Jiang (do-not-use), Yuhang Wang, Tao Jiang, Zhiyu Zhao, Kin Lam, Shashank Pant, Archit Vasan, Nandan Haloi, Sepehr Dehghanighahnaviyeh, Karanpal Kapoor, Zhaleh Ghaemi

From bacteria to mammals, different phospholipid species are distributed asymmetrically between the two leaflets of the cellular membrane. Disruption of this asymmetry is a ubiquitous signaling mechanism essential for critical cellular events such as cell activation, coagulation, and apoptosis. Proteins responsible for phospholipid scrambling belong to the TMEM16 superfamily of membrane proteins, which are functionally split into (1) dual function scramblases/nonselective ion channels and (2) Cl^- channels. The recently published structures of the TMEM16 members provide a unique opportunity to explore the complex and diverse functions of the superfamily and the underlying mechanisms through molecular dynamics (MD) simulations. Here, we propose to employ extensive MD simulations coupled with umbrella sampling free energy calculations to investigate the translocation mechanism and pathway of the two types of fundamentally important substrates transported by the TMEM16 superfamily, namely phospholipids and ions. The goal is to characterize the free energy landscape governing the substrate translocation and to gain insight into the functional relationship between different superfamily members. The calculation of free energies requires massive computing resources, thus can only be realized on petascale platforms such as Blue Waters. This project will greatly enhance our understanding of the mechanistic details of a superfamily that is of broad physiological and biomedical relevance.