Deletion of the 13 C-terminal residues of the 149 residue staphylococcal nuclease (SNase) molecule results in a denatured, partially unfolded molecule (SNase Delta) that is relatively compact under physiological conditions. We have performed molecular dynamics simulations of wild type SNase and SNase Delta at 300 K in aqueous solution. Whereas the wild type preserved its native three-dimensional architecture, the truncated form significantly denatures over the 500 ps simulation period. The denaturation leads to significant rearrangements in the inhibitor binding pocket and is in general accord with conformation-dependent chemical cleavage experiments. SNase Delta thus provides a system in which protein denaturation can be examined using molecular dynamics under experimental conditions and at physiological temperatures.