The chemical reactivities of lysyl, tyrosyl and methionyl residues in subtilisin DY are compared with the computed accessibilities to the water molecules of the corresponding sensitive atoms in the crystal structure of subtilisin Carlsberg. A good correlation between accessibilities and reactivity was established for the nonionized specific reagents glyceraldehyde and chloramine T used for modification of lysine and methionine residues, respectively. In a few cases an apparent deviation from the general relationship was established. The disagreement may indicate that differences between crystal and solution structures exist with altered accessibilities of the atoms under consideration. However, when an electrically charged system takes part in the reaction and it is in low concentration, as in the case of tetranitromethane treatment where the phenoxylate anion reacts, the correlation is more complex. In this case not only the accessibility, but also the electrostatic field around the reacting group, should be taken into account for the explanation of the reaction observed.