Biophysical Society Thematic Meeting | Hamburg 2022

Biophysics at the Dawn of Exascale Computers

Thursday Speaker Abstracts

PUSHING THE TIME SCALE OF MEMBRANE PERMEABILITY CALCULATIONS An Ghysels 1 ; 1 Ghent University, IBiTech - Biommeda group, Gent, Belgium Membrane permeability is a crucial property for the delivery of chemical compounds, nutrients, and drug molecules. For instance, the last barrier for oxygen to reach its final destination, the binding site located on the cytochrome c oxydase in the mitochondrial membrane, is the entrance into the bilayer.[1,2] While this step cannot be observed directly in experiment, oxygen trajectories can be generated with molecular dynamics simulations. A methodology based on the Smoluchowsky equation was derived to extract the dynamics of oxygen permeation from these trajectories using Bayesian analysis (BA).[3] The results of the methodology are the free energy across the membrane, and the diffusion profiles normal and parallel to the membrane surface. From these profiles, the permeability and the characteristic entrance, transit, and escape times as well as characteristic lengths have been derived for a model of the inner mitochondrial membrane. Analysis of other saturated and unsaturated phospholipid membranes in the liquid phase show little difference, while a noticeable reduction of the permeability is found in liquid ordered phases.[4]The described BA methodology has the advantage that radial diffusion can be analyzed. More importantly, multiple short trajectories can be used for the permeability calculation, whereas a strategy of counting membrane transitions would need very long trajectories for a simple hydrophilic molecule like oxygen. For a hydrophobic molecule like water, however, the BA methodology has also convergence issues. Therefore we explore a new methodology, where the intrinsic kinetics may be retrieved from an accelerated molecular dynamics simulation. Moreover, we present another new methodology based on a divide-and- conquer strategy using sampling that can assess the exact kinetics of the permeation event, i.e. without assuming diffusive kinetics in the membrane.[5]References[1] Riistama et al. Biochim. Biophys. Acta, Bioenerg. 1-4, 1 (1996).[2] Wikstrom et al. Chem. Rev. 115, 2196-2221 (2015).[3] Ghysels et al. J. Chem. Theory Comput. 13, 2962-2976 (2017).[4] Ghysels et al. Nat. Commun. 10, 5616 (2019).[5] Riccardi et al. J. Phys. Chem. B, 125, 1, 193-201 (2021).

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