Strong and Weak Hydrogen Bonds in Protein–Ligand Recognition

Abstract

The hydrogen bond has justifiably been termed the ‘master key of molecular recognition’. It is an interaction that is weaker than the covalent bond and stronger than the van der Waals interaction. The ubiquity and flexibility of hydrogen bonds make them the most important physical interaction in systems of biomolecules in aqueous solution. Hydrogen bonding plays a significant role in many chemical and biological processes, including ligand binding and enzyme catalysis. In biological processes, both specificity and reversibility are important. Weaker interactions can be made and broken more easily than stronger interactions. In this context, it is of interest to assess the relative significance of strong and weak interactions in the macromolecular recognition processes. Is protein–ligand binding governed by conventional, that is, electrostatic N–H…O and O–H…O hydrogen bonds, or do weaker interactions with a greater dispersive component such as C–H…O hydrogen bonds also play a role? If so, to what extent are they significant? Most proteins, involving as they do, main chains, side chains, and differently bound forms of water, do not really have a static fixed structure, but rather have a dynamic, breathing nature. This tendency may to some extent be lessened by the ligands which are small molecules, but in the end, it is reasonable to expect that the strong and weak hydrogen bonds inside the protein and also at the protein–ligand interface will also have dynamic character; arguably, the weaker the hydrogen bond, the greater its dynamic character. These are often central to the much debated mechanisms of binding such as conformational selection and induced fit. All protein–ligand interactions must compete with interactions with water; both the protein and the ligand are solvated before complexation and lose their solvation shell on complex formation. Conversely, the entropic cost of trapping highly mobile water molecules in the binding site is large. However, in favorable cases, these losses are suitably compensated by the enthalpic gain resulting from water-mediated hydrogen bonds. In effect, the enthalpy–entropy balance is a fine one, and for a water molecule to be able to contribute to binding affinity, it has to be in a binding site that provides the maximum number of hydrogen-bond partners at the optimum distance and orientation. In summary, hydrogen bonds are crucial to the recognition of ligands by proteins. Integration of knowledge gained from more high-quality protein–ligand structures into theoretical and computational molecular models will be an exciting challenge in the coming years.