Voltage-gated sodium channels are essential for the initiation and propagation of action potentials. Na V 1.5, the predominant sodium channel isoform in cardiac muscle, is critical for maintaining cardiac excitability and has been implicated in a wide spectrum of arrhythmogenic disorders. Genomic analyses from a pharmacogenomics database PGxDB and genome aggregation database (gnomAD) have identified multiple Na V 1.5 mutations linked to Brugada syndrome and other inherited arrhythmias, and a few of these mutations reduce or abolish sodium current. To uncover the molecular mechanisms underlying altered physiology and pharmacology of these pathogenic variants, we employ molecular dynamics (MD) simulations to examine how mutations alter channel structure, gating, and drug binding. Complementary drug-docking studies further evaluate the interactions between Na V 1.5 and clinically relevant antiarrhythmic compounds. We tested several potentially pathogenic Na V 1.5 pore-domain mutants via MD simulations as well as AutoDock4 and OpenEye FRED drug docking and found that these mutations affect channel structural stabilities and anti-arrhythmic drug quinidine binding. We will expand those studies to a wider set of Na V 1.5 mutants and sodium channel binders. We will also test how auxiliary protein 14-3-3 binding affects channel gating and drug binding for both wild-type and mutant Na V 1.5 channels. By integrating mutation-specific structural insights with computational drug screening, this work aims to support precision medicine, tailoring antiarrhythmic therapy to a patient’s molecular genetic profile. In the long term, insights from these simulations may contribute to the development of digital twin heart models, enabling individualized prediction of drug efficacy and safety to optimize clinical treatment.
Lai et al. (Sun,) studied this question.