Results reporting on the computational efficiency of the original and the optimized cholesterol models in the phase separating lipid bilayer are listed in Table . For details about the overall hardware configuration and the efficiency of the β 2 AR-containing simulations, we refer to section 5 of the Supporting Information and Table , respectively. For given settings, MD simulations with the optimized cholesterol model incurred a performance penalty of ≈ 10 -15% in all cases. Because this comparison does not take into account whether the physics of the system is correct or not, we also compared the performance of the previously recommended parameters for proper LINCS convergence, (lincs iter=2, lincs order=12, ∆t = 20 fs) and (lincs iter=3, lincs order=12, ∆t = 30 fs). Requiring the temperature gradient to be negligible (|∆T | < 2 K, based on the convergence of properties in Figure ), one needs to perform simulations of the original model at ∆t = 20 fs using lincs iter=2, lincs order=12 resulting in 1623 ns/day, while it suffices to run the optimized model using lincs iter=1, lincs order=4 which allows the simulation of 1752 in ≈ 30% performance increase compared to stricter LINCS settings 10 (see Table ). The representation of a rigid topology by two connected triangular constraints, the socalled hinge model, as it is used in cholesterol, served as a blueprint for the Martini 3 topologies of a number of small molecules. Therefore, we assessed the quality of the constraint topology in terms of λ max for 77 constrained Martini 3 small molecules 17 (available at ) by estimating the required LINCS order for convergence and by performing explicit simulations (see Tables ).