Ligand-Binding Free Energy Simulations of Membrane Proteins.

Molecular modeling and simulations of biomolecular systems are crucial for understanding their structure, dynamics, and function. They also play a key role in drug discovery and design, since protein-ligand affinity is a critical factor in developing new drugs. This chapter primarily focuses on computational methods for predicting ligand-binding affinity in membrane proteins. It highlights the major challenges associated with calculating ligand affinities in membrane protein environments and discusses potential solutions. Various membrane protein systems are presented to demonstrate the capabilities of both geometric and alchemical approaches in accurately estimating ligand-binding affinities. Free energy methods such as free energy perturbation (FEP), thermodynamic integration (TI), the alchemical transfer method (AToM), umbrella sampling (US), and weighted ensemble (WE) have been successfully applied to GPCRs, ion channels, and transporters, with representative examples discussed throughout the chapter.