Biophysical Society Conference | Tahoe 2024

Molecular Biophysics of Membranes

Thursday Speaker Abstracts

SYSTEMATIC COMPUTATIONAL ANALYSIS OF LIPID SCRAMBLING BY TMEM16 FAMILY MEMBERS Niek van Hilten 1 ; Yisheng Zheng 1 ; Christina A Stephens 1 ; Michael Grabe 1 ; 1 University of California, San Francisco, San Francisco, CA, USA Calcium-activated TMEM16 proteins play important roles in eukaryotes through their passive ion transport and lipid scrambling activity. In fact the latter has been associated with blood coagulation, viral entry, and cancer. Experimental and simulation studies have demonstrated that both mammalian and fungal TMEM16 members scramble lipids by inducing a strong membrane deformation near a hydrophilic groove that facilitates lipid translocation in a “credit-card” like mechanism. However, given the variety of identified calcium-bound conformations, individual members may scramble in different ways. Here, we employ systematic coarse-grained molecular dynamics simulations on every available TMEM16 structure to address important open questions about open/closed states, scrambling pathways, and lipid specificity. This study highlights the similarities and differences between the different family members and will help us better understand the different physiological roles of these proteins in both health and disease.

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