Ionizable residues are rarely present in the hydrophobic interior of proteins, but when they are, they play important roles in biological processes such as energy transduction and enzyme catalysis. Internal ionizable residues have anomalous experimental pK(a) values with respect to their pK(a) in bulk water. This work investigates the atomistic cause of the highly shifted pK(a) of the internal Glu23 in the artificially mutated variant V23E of Staphylococcal Nuclease (SNase) using pH replica exchange molecular dynamics (pH-REMD) simulations. The pK(a) of Glu23 obtained from our calculations is 6.55, which is elevated with respect to the glutamate pK(a) of 4.40 in bulk water. The calculated value is close to the experimental pK(a) of 7.10. Our simulations show that the highly shifted pK(a) of Glu23 is the product of a pH- dependent conformational change, which has been observed experimentally and also seen in Our simulations. We carry out an analysis of this pH-dependent conformational change in response to the protonation state change of Glu23. Using a four-state thermodynamic model, we estimate the two conformation-specific pK(a) values of Glu23 and describe the coupling between the conformational and ionization equilibria.