A model for the complete sequence of the human voltage-gated calcium channel (CaV1.2) in a lipid bilayer.

During the past decade, advancements in CryoEM have afforded significant insight into transmembrane regions of ion channels. Portions of cytosolic amino acids have been structurally and biophysically characterized; however, understanding structural relationships and how components integrate into a functional ion channel required clarification. Here, we have calculated an all-atom model for the complete sequence of the cardiac voltage-gated calcium ion channel (CaV1.2 alpha-1C and beta-3 subunits) in a lipid bilayer with explicit salt and water. Four one-microsecond molecular dynamics (MD) simulations of the isolated alpha subunit improved backbone torsion angles for non-transmembrane residues relative to the AlphaFold model. Two 500 ns MD simulations of CaV1.2 (alpha and beta subunits) provided insight into the binding interface and structural features of the complex. The time component of our MD simulation provided unique insight into side chain dynamics, solvation of voltage sensors, and features of the channel pore. Repeating the alpha subunit simulations with a highly penetrant Timothy Syndrome point mutation (G406R) predicted changes to side chain dynamics that may contribute to a destabilization mechanism of an inactivated channel configuration. Lastly, a comparison of our WT post-MD model with empirical data obtained in the presence of small molecules yielded mechanistic insights into several small molecule CaV1.2 interactions.