pH is a critical parameter for biological and technological systems directly related with electrical charges. It can give rise to peculiar electrostatic phenomena, which also makes them more challenging. Due to the quantum nature of the process, involving the forming and breaking of chemical bonds, quantum methods should ideally by employed. Nevertheless, due to the very large number of ionizable sites, different macromolecular conformations, salt conditions, and all other charged species, the

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... PU time cost simply becomes prohibitive for computer simulations, making this a quite complex problem. Simplified methods based on Monte Carlo sampling have been devised and will be reviewed here, highlighting the updated state-ofthe-art of this field, advantages, and limitations of different theoretical protocols for biomolecular systems (proteins