Salt bridge (protein)

In chemistry, a salt bridge is a combination of two noncovalent interactions: hydrogen bonding and electrostatic interactions (Figure 1). This is most commonly observed to contribute stability to the entropically unfavorable folded conformation of proteins. Although noncovalent interactions are known to be relatively weak interactions, small stabilizing interactions can add up to make an important contribution to the overall stability of a conformer. Not only are salt bridges found in proteins, but they can also be found in supramolecular chemistry. The thermodynamics of each are explored through experimental procedures to assess the free energy contribution of the salt bridge to the overall free energy of the state.

The salt bridge most often arises from the anionic carboxylate (RCOO⁻) of either aspartic acid or glutamic acid and the cationic ammonium (RNH₃⁺) from lysine or the guanidinium (RNHC(NH₂)₂⁺) of arginine (Figure 2). Although these are the most common, other residues with ionizable side chains such as histidine, tyrosine, and serine can also participate, depending on outside factors perturbing their pK_a's. The distance between the residues participating in the salt bridge is also cited as being important. The distance required is less than 4 Å (400 pm). Amino acids greater than this distance apart do not qualify as forming a salt bridge. Due to the numerous ionizable side chains of amino acids found throughout a protein, the pH at which a protein is placed is crucial to its stability.

The contribution of a salt bridge to the overall stability to the folded state of a protein can be assessed through thermodynamic data gathered from mutagenesis studies and nuclear magnetic resonance techniques. Using a mutated pseudo-wild-type protein specifically mutated to prevent precipitation at high pH, the salt bridge’s contribution to the overall free energy of the folded protein state can be determined by performing a point-mutation, altering and, consequently, breaking the salt bridge. For example, a salt bridge was identified to exist in the T4 lysozyme between aspartic acid (Asp) at residue 70 and a histidine (His) at residue 31 (Figure 3). Site-directed mutagenesis with asparagine (Asn) (Figure 4) was done obtaining three new mutants: Asp70Asn His31 (Mutant 1), Asp70 His31Asn (Mutant 2), and Asp70Asn His31Asn (Double Mutant).

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