Biophysical Society Thematic Meeting | Hamburg 2022

Biophysics at the Dawn of Exascale Computers

Poster Abstracts

58-POS Board 58 A NEED FOR EXASCALE MODELING OF MEMBRANE FUSION IN THE PRESENCE OF GENERAL ANESTHETICS Dixon J. Woodbury 1 ; Robert E Coffman 1 ; 1 Brigham Young University, Neuroscience Center, Provo, UT, USA General anesthetics have been used for over 175 years, and many cellular targets have been identified as possible sites of action. Most modes of action assume that anesthetics enter the membrane and either act directly by loosely binding to a membrane protein (Hemmings, et al., 2019. Trends Pharmacol Sci. 40:464-481), or act indirectly by increasing the lateral pressure that the membrane’s hydrophobic core applies to membrane proteins (Cantor, 1997. Biochemistry 36:2339-2344). Either way, it is assumed that loss of synaptic function is due to modulation of critical protein functions. Using a protein-free assay for exocytosis, we have reported a possible mode of anesthetic action that does not fit with the protein model (Paxman et al., 2017. Biophysical J. 112:121-132). The data with short-chain alcohols suggest that alcohols alter the activation energy of membrane-membrane fusion. This could be by promoting dehydration of the fusing membranes (loose-to-tight docking) or by enhancing lipid tail splay (leading to hemifusion) (Witkowska et al., 2021. Nat Commun 12:3606). Both are mechanisms whereby synaptic transmission could be modulated by anesthetics in a protein-independent way. Few experimental systems lend themselves to study this process in vitro, and no in vivo system can be made free of proteins. Therefore, an all-atom simulation appears to be one of just a few paths forward to identify the mechanism of action for alcohols on membrane fusion. To model correctly the effect of different alcohols and anesthetics on the dehydration process, the system would likely need 1000’s of lipids. Coarse-grain simulations cannot be used, since the data show that ethanol and methanol had opposite effects on membrane fusion. Calculations on the exascale will likely be required to study this process with sufficient atoms and over 100’s of microseconds.

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