It is often assumed that only neutral molecules partition into and passively permeate across biological membranes. Although there is mounting evidence that these processes are also facile for some charged species, it is unknown whether or not such ionizable permeants dynamically neutralize at the membrane surface or actually permeate in their charged form. Understanding the coupling between dynamic ionization and membrane permeation, however, requires a multiscale approach that describes local molecular scale protonation changes, the larger thermodynamics of permeation via enhanced sampling, and macroscopic quantification permeabilities. In this talk, I will describe our recent extension of continuous constant-pH molecular dynamics to probe protonation-coupled permeation in atomic detail via the membrane<br/>permeation of a weak base propranolol (PPL). This work reveals how PPL migrates into lipid bilayer in a charged form, deprotonates before entering the hydrocarbon tails, and then reprotonates upon exiting the tail region of the other membrane leaflet. I will explain how a<br/>conventional non-ionizable model drastically underestimates the number of the permeable molecules and thus overestimates the assigned intrinsic permeability based on the experimentally observed effective permeability. I will present a revised model that better describes the pHcoupled partitioning and permeation, and demonstrate how dynamic protonation predicts a permeability for PPL directly from simulations in excellent agreement with experiment. I will close with a discussion of how constant-pH molecular dynamics might be combined with<br/>reactive dynamics in a multiscale fashion to further probe coupled protonation processes.

Integrating dynamic ionization into membrane permeation free energy landscapes and macroscopic permeability calculations

2019 Fall National Meeting

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