While it has been known for some time that lipids can directly bind to and allosterically modulate membrane proteins, measuring a lipid’s binding affinity remains a challenge. Molecular dynamics (MD) simulations represent a promising vehicle for reliably measuring this quantity, but current solutions either utilizes complicated biasing procedures or ignore the unreliable kinetics inherent in most coarse-grain (CG) models. We previously introduced the density-threshold affinity (DTA), a technique for measuring a lipid’s binding affinity from unbiased CG-MD simulations. In the present work, we use an expanded DTA toolkit to investigate two lipid interactions with pLGICs: arachidonic acid (AA) inhibiting the nicotinic acetylcholine receptor (nAChR), and cardiolipin (CDL) rescuing the resting state of a prokaryotic ion channel (ELIC5). We demonstrate that AA binds to an intrasubunit site on the nAChR and effectively saturates the subunits at conditions matching those reported in experiment. We also show that cardiolipin biases the ensemble of states toward the resting state by binding to an intrasubunit site on ELIC5. Calculation of binding affinities, occupancy predictions, and comparisons across experimental conditions are all enabled by the DTA GUI, making these types of calculations easily accessible to other teams.
Sandberg et al. (Sun,) studied this question.