Molecular dynamics simulations of membrane protein - ligand interactions: from empirical force fields to heart rhythm predictions

Membrane proteins are embedded into hydrated lipid membranes and play a number of important biological roles in living organisms serving roles as channels, transporters, and receptors to name a few. Their biological activity is being regulated by a variety of small-molecule and peptide ligands as well as lipid membrane composition. A complex interplay of electrostatic and van der Waals forces plays a major role in membrane protein - ligand interactions and modulates membrane protein function. Atomistic molecular dynamics (MD) is an excellent tool to investigate and quantify those effects. It is based on classical empirical force fields for constituent molecules and empowered by latest advances in computer hardware and enhanced sampling MD simulation methods. I will discuss several examples of membrane protein - ligand interactions, which we investigated using atomistic MD simulations. They include voltage-gated potassium channel hERG interactions with drug molecules, which play a key role in drug-induced cardiac arrhythmia. I will also discuss interactions of peptide toxin protoxin-II with the voltage-sensing domains of voltage-gated sodium channels, crucial for the development of novel effective treatments for chronic pain and cancer. I will also talk about ligand interactions with beta-adrenergic receptors, which are key players in the sympathetic nervous system stimulation.  I will discuss major achievements and challenges of using atomistic MD simulations to study those membrane protein - ligand systems. Finally, I will talk about how we can link data from those atomistic MD simulations to multiscale kinetic models of cardiovascular and nervous system functions to predict emergent effects of drugs, toxins and sympathetic drive on heart rhythm.