We review foundations of biomolecular simulations that enable the study of membrane protein models with a particular focus on structure–function relationships and opportunities for drug design. A range of broadly used methods is presented comprising homology modeling, normal mode analysis, molecular dynamics simulations, and free energy calculations. These methods are illustrated with examples on several membrane protein systems, in particular ligand-gated ion channels such as the P2X receptors, the N-methyl-D-aspartate (NMDA) receptors, and the Cys-loop family of pentameric ion channels.