ABSTRACT
The protonation state of amino acid residues in proteins depends on their respective pK a values. Computational methods are particularly important for estimating the pK a values of buried and active site residues, where experimental data are scarce. In this work, we used the cluster model approach to 252 predict the pK a of some challenging protein residues and for which methods based on the numerical solution of the Poisson‐Boltzmann equation and empirical approaches fail. The ionizable residue and its close environment were treated by quantum mechanics, while the rest of the protein was replaced by a uniform dielectric continuum. The approach was found to overestimate the electrostatic interaction, leading to predicting lower pK a values.
