( A solution for this case would be to use smaller Martini water models. Small and tiny sized Martini 3 water beads already exist (which represent 3 to 1 and 2 to 1 all-atom molecules to a water bead, respectively), but there are no clear solutions on how to restrain these smaller water beads to the protein interface. Usage of small and tiny water beads as pure solvents is discouraged, as they are still not fully parameterized with this use case in mind. Moreover, using pure solvents made up of small or tiny beads substantially increases simulation particle count, impacting the simulation speed-up advantage of Martini 3 over conventional all-atom Martini 3 approach of restraining side chain conformations based on the starting structure (using the ScFix method ) is sub-optimal, and fitting residue-specific side chain dihedral potentials could further improve the Martini 3 protein model. While ScFix is a definite requirement in the current Martini 3 protein model, future developments should aim to remove the need for such biases, albeit this is complicated by distinct environment-dependent rotamer distributions between soluble and transmembrane proteins. Overall, a combination of several factors, ranging from packing, interaction balance, water model, and electrostatics, may be behind the current issues regarding Martini 3 soluble protein complexes. Future developments regarding the protein model will focus on mitigating some of these limitations, but for now, current iterations of the Martini 3 protein model will require biases applied to the quaternary network, like OLIVES, to better reproduce soluble complexes.