Here, we use the direct enthalpy calculation method to estimate the relative binding enthalpies of constrained and flexible phosphopeptides for the SH2 domain of growth factor receptor protein 2 (Grb2) . As perhaps expected, the more rigid, and hence better preorganized, constrained peptides were found experimentally to bind the protein with higher affinity . Unexpectedly, however, their greater affinity traces to a more favorable binding enthalpy, instead of the entropic advantage anticipated due to their preorganization .