Strong and Weak Hydrogen Bonds in Protein– Ligand Recognition

Gopalakrishnan Bulusu, Gautam R. Desiraju


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.


Biomolecular recognition, Supramolecular synthon, Drug–receptor, Enthalpy–entropy, Drug design, Hydration


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