With a structural bioinformatic approach, we have explored amino acid compositions at PISA defined interfaces between small molecules and proteins that are contained in an optimized subset of 11,351 PDB files. The use of a series of restrictions, to prevent redundancy and biases from interactions between amino acids with charged side chains and ions, yielded a final data set of 45,230 protein-small molecule interfaces. We have compared occurrences of natural amino acids in surface exposed regions and binding sites for all the proteins of our data set. From our structural bioinformatic survey, the most relevant signal arose from the unexpected Gly abundance at enzyme catalytic sites. This finding suggested that Gly must have a fundamental role in stabilizing concave protein surface moieties. Subsequently, we have tried to predict the effect of in silico Gly mutations in hen egg white lysozyme to optimize those conditions that can reshape the protein surface with the appearance of new pockets. Replacing amino acids having bulky side chains with Gly in specific protein regions seems a feasible way for designing proteins with additional surface pockets, which can alter protein surface dynamics, therefore, representing controllable switches for protein activity.