Ionizable residues in the hydrophobic interior of certain proteins are known to play important roles in life processes like energy transduction and enzyme catalysis. These internal ionizable residues show experimental apparent pK(a) values having large shifts as compared to their values in solution. In the present work, we study the pH-dependent conformational changes undergone by two variants of staphylococcal nuclease (SNase), L25K and L12SK, using pH replica exchange molecular dynamics (pH-REMD) in explicit solvent. Our results show that the observed pK(a) of Lys2S and Lys125 are significantly different than their pK(a) in solution. We observed that the internal lysine residues prefer to be water-exposed when protonated at low pH, but they remain buried within the hydrophobic pocket when deprotonated at high pH. Using thermodynamic laws, we estimate the microscopic conformation-specific pK(a) of the water-exposed and buried conformations of the internal lysine residues and explain their relation to the macroscopic observed pK(a) values. We present the differences in the microscopic mechanisms that lead to similar experimentally observed apparent pK(a) of Lys2S and Lys125, and explain the need of thermodynamic models of different complexities to account for our calculations. We see that L25K displays pH-dependent fluctuations throughout the entire beta barrel and the alpha 1 helix. In contrast, pH-independent fluctuations are observed in L125K, primarily limited to the alpha 3 helix. The present computational study offers a detailed atomistic understanding of the determinants of the observed anomalous pK(a) of internal ionizable residues, bolstering the experimental findings.