Many amino acid side chains can gain or lose protons (a process known as ionisation) meaning that the charge of an amino acid residue is dependent on the pH of its environment.

The pKa of a side chain is defined as the pH at which 50% of the side chain is protonated (has a hydrogen attached) and 50% is deprotonated (has lost a hydrogen). The relationship between pH and pKa determines whether a side chain is charged.

When the pH is lower than the pKa, the side chain is predominantly protonated, resulting in acidic residues being neutral and basic residues carrying a positive charge:

pH < pKa → protonated 

(acids neutral, bases positively charged)

When the pH is higher than the pKa, the side chain is predominantly deprotonated, resulting in acidic residues being negatively charged and basic residues being neutral:

pH > pKa → deprotonated 

(acids are negatively charged, bases are neutral)

Changes in ionisation state directly influence electrostatic interactions, hydrogen bonding, and the formation of salt bridges, all of which affect protein structure, stability and activity. 

Importantly, a residue’s effective pKa can shift depending on whether it is solvent-exposed or buried, and what charges sit nearby. A practical takeaway is: if a charged residue is buried or sits in an unusual environment, its behaviour may be atypical, and that can matter for activity, binding, and stability.

At pH 7, the amino and carboxyl groups are charged, but over a pH range from 1 to 14 these groups exhibit a series of equilibria involving binding and dissociation of a proton. The binding and dissociation of a proton reflect the role of these groups as weak acids or weak bases. The acid–base behaviour of amino acids is important because it influences the eventual properties of proteins, enables methods of identification for different amino acids, and dictates their reactivity.