salt bridge

A salt bridge is a charged 'best-of-both-worlds' contact: it is an ionic attraction and a hydrogen bond rolled into one. Imagine a positively charged amine on the drug nestling against a negatively charged carboxylate on the protein — they pull together by charge, and at the same time the amine's N–H points right at the carboxylate's oxygen to form a hydrogen bond. The result is a tight, highly directional anchor.

Because it combines two favorable interactions, a buried salt bridge can contribute strongly to both affinity and specificity, and is often a key 'pin' that fixes the orientation of a ligand in its pocket. Common partners are protonated basic groups (amines, guanidiniums) on one side and carboxylates, phosphates or sulfonates on the other.

The honest caveat is that salt bridges are expensive to form in water. Each partner must first shed its tightly bound shell of water and counter-ions, which costs energy, so the net benefit can be smaller than the raw electrostatics suggest — especially for a salt bridge left exposed to solvent rather than buried. They pay off most when deeply shielded from water inside the protein.