A point substitution of the oxygen is selected to weaken the interaction of the N-O-N neighborhood. To preserve the electronic structure of BAM-15 and its lone pairs a sulfur atom is used. This preserves the proton transport properties coming from the homogenous and heterogenous aromatic rings and the amines. The sulfur substitution knocks out the presence of the 1 st highest binding mode completely, as seen in Figure Substitution of the oxygen with an N nitrogen (a triazoline type molecule) includes the addition of a hydrogen and generates 2 tautomers. One of the tautomers eliminates the highest binding mode and generates a lower binding than substitution with sulfur. Its score distribution is shown in Figure . This example was selected to present because it shows a common phenomenon in interaction distributions: The states between 73.7 and it's highest score of 79.3 (a wide 5.6 separation) are sparsely populated. This comes from high specificity in the binding potential for the ligand to dynamically move into. In extreme conditions with long relaxation times such as in crystal structure formation for x-ray measurements, or at very low temperature, these states may be populated in a protein-ligand bound complex. In general conditions, however, the specificity of the potential is too restrictive and on biochemical time scales the highest thermally populated state is physically ~73.7. This still seems very good as the score is much smaller and BAMN-15 has much decreased interaction, a score difference of 13.6 or 2.1 kcal (x100). However, there is a tautomer of this molecule of lower internal bond energy and it binds with the approximate strength of BAM-15, Figure .