The lock and key model for Molecular Recognition. Is it time for a paradigm shift?

Abstract: We review the standard lock and key (LK) model for binding small ligands to larger adsorbent molecule. We discuss three levels of the traditional LK model for binding. Within this model the binding constant or the Gibbs energy of the binding process is related to the total interaction energy between the ligand and the binding site of the adsorbent molecules. When solvent molecules are present, which is the case in all binding processes in biochemistry, we find that a major part of the Gibbs energy of binding could be due to interactions mediated through the solvent molecules. This finding could have major consequences to the applicability of the LK model in drug design, and perhaps require a shift in the prevailing paradigm in this field of research. Keywords: Lock and key model, Binding constant, solvent effect on binding, hydrophilic effect, molecular recognition.