Molecular dynamics of membrane partitioning of nifedipine prior to binding calcium channel Cav1.1

An increasing number of ligand-bound membrane protein structures reveal ligand-binding sites on the lipid-exposed surface of the protein within the membrane bilayer. Binding events to such sites have previously been studied using molecular dynamics (MD) simulations and experiments in cases such as calcium-gated potassium channels1 and sodium channels2. The proposed binding mechanism is that these ligands partition into the membrane to gain access to their binding site. What is currently unavailable is what the thermodynamic and kinetic contributions of the ligand-membrane and ligand-protein interactions are to the overall binding event. Here, we used MD simulations and enhanced sampling methods to study the membrane partitioning of a DHP calcium channel antagonist, nifedipine, from the voltage-gated calcium channel Cav1.1. We present that drug-membrane interactions occur on a much faster timescale than the overall binding of nifedipine to Cav1.1.