It is important to note that kinetic processes in Martini, such as the binding and unbinding of cholesterol, are not always correctly recovered. If a process is dominated by enthalpic contributions, such as in the case of cholesterol flip-flop, Martini should recover reasonable kinetics. However, in entropy dominated processes, such as in diffusional-based mechanisms, the kinetics are often substantially sped up due to the missing atomistic degrees of freedom. While the binding/unbinding of cholesterol to a protein in a membrane context, has a non-negligible enthalpic contribution (enthalpic competition between cholesterol and lipid acyl chains for the binding site), it also has a substantial entropic contribution (cholesterol diffusion in and out of the binding site, side-chain reorientation) which will be sped up in Martini. It must also be mentioned that residency times vary substantially due to system setup (force field, temperature, Chol mol%, lipid composition, etc.) and the analysis method used. One last aspect that could potentially impact cholesterol binding, is the overall hydrophobicity of the protein model. Growing evidence hints that the Martini 3 protein model may be too hydrophilic 139-141 , as seen by typical transmembrane peptides being ejected to the membrane periphery. If this is the case, it is likely that interactions with hydrophobic molecules, such as cholesterol, may be slightly impacted. Nonetheless, with enough sampling, interaction sites are expected to remain mostly consistent between Martini 3 and Martini 2 and in agreement with AA data, albeit with more dynamic interactions.