Tuning of hydrogen bond strength using substituents on phenol and aniline: a possible ligand design strategy

Using Density Functional Theory, the hydrogen bonding energy is calculated for the interaction of phenol and aniline with four model compounds representing the protein backbone and various amino acid side chain residues. The models are methanol, protonated methylamine, formaldehyde and acetate anion. The H-bond energies for the uncharged species are approximately 2.5 kcal mol(-1), whereas the charged model compounds bind with much higher energies of approximately 20 kcal mol(-1). The effect of para-substitution on the hydrogen bond energies is determined. Substitution has little effect on the H-bond energy of the neutral complexes (<2 kcal mol(-1)), but for the positively and negatively charged systems substitution drastically alters the binding energies, e.g., 14.3 kcal mol(-1) for para-NO2. In the context of protein-ligand binding, relatively small changes in binding energy can cause large changes in affinity due to their exponential relationship. This means that for -NO2 an enormous change of 10 orders of magnitude for the affinity constant is predicted. These calculations allow prediction of H-bonds, using different substituents, in order to fine-tune and optimize ligand-protein interactions in the search for drug candidates.