Dmpc pro 1.0.2
We developed the positively charged (cationic) and neutral d-sotalol models, compatible with the biomolecular CHARMM force field, and subjected them to all-atom molecular dynamics (MD) simulations of drug partitioning through hydrated lipid membranes, aiming to elucidate thermodynamics and kinetics of their translocation and thus putative propensities for hydrophobic and aqueous hERG access. As a proof of principle, we evaluated extensively lipid membrane partitioning of d-sotalol, well-known blocker of a cardiac potassium channel K v11.1 encoded by the hERG gene, with reported substantial proclivity for arrhythmogenesis. All-atom molecular simulations may help to map drug partitioning kinetics and thermodynamics, thus providing in-depth assessment of drug lipophilicity. Very little is known about spatial localization of various drugs in the lipid bilayers, their active form (ionization state) or translocation rates and therefore potency to bind to different sites in membrane proteins. Interactions of drug molecules with lipid membranes play crucial role in their accessibility of cellular targets and can be an important predictor of their therapeutic and safety profiles. 5Centre for Molecular Simulations, Department of Biological Sciences, Faculty of Science, University of Calgary, Calgary, AB, Canada.4Hartnell College, Salinas, CA, United States.3Biophysics Graduate Group, University of California, Davis, Davis, CA, United States.2Department of Pharmacology, University of California, Davis, Davis, CA, United States.1Department of Physiology and Membrane Biology, University of California, Davis, Davis, CA, United States.DeMarco 1,2,3, Slava Bekker 1,4, Colleen E.