The peptidyl-prolyl isomerase CypA catalyzes the cis/trans isomerization of the amide preceding proline residues in proteins, inducing a structural change in peptide chains that would otherwise be extremely slow under physiological conditions. This fundamental catalyst for protein conformational change is ubiquitously expressed and plays a role in a wide variety of biomolecular mechanisms, including protein folding, trafficking, and signalling and regulation. Equally, however, CypA has been implicated in a wide variety of disease processes, particularly the facilitation of viral infection and replication. Owing to this broad spectrum of activity and therapeutic interest, CypA structure, dynamics and catalytic mechanism have been well-studied for decades using both experimental and computational structural biology approaches. Many of these studies have identified residue R55, conserved across the cyclophilin family, as mechanistically crucial -either a R55A or R55K mutation result in a similar reduction of catalytic efficiency. In the case of the lysine mutation this change in activity occurs in spite of little structural perturbation of the active site. A subtle combination of electrostatic, structural and/or dynamical effects has therefore long been thought to underlie the contribution of R55 to catalysis.