Calmodulin readily switches conformation upon protonating high pK(a) acidic residues

Official URL: http://dx.doi.org/10.1021/jp3032995

We investigate protonation as a possible route for triggering conformational change in proteins by focusing on the calmodulin (CaM) example. Two hundred nanosecond molecular dynamics (MD) simulations are performed on both the extended and compact forms of calcium loaded CaM. The stability of both structures is confirmed under prevailing conditions. Protonation of nine acidic residues with upshifted pK(a) values leads to a large conformational change in less than 100 ns. The structure attained is consistent with fluorescence resonance energy transfer experimental results as well as structures from an ensemble compatible with NMR data. Analysis of the MD trajectories summing up to one microsecond implies that the key events leading to the completion of the conformational change begins with an initial formation of a salt bridge between the N-lobe and the linker, followed by the bending of the C-lobe and the organization of a stabilizing hydrophobic patch between the lobes. We find that CaM utilizes its Ca2+ ions to harden/soften different regions so as to achieve various conformations. Thus, barrier crossing between extended and compact forms of CaM which is normally a rare event due to the repulsive electrostatic interactions between the two lobes is facilitated by protonation of high pK(a) residues. The results delineate how pH changes might be utilized in the cell to achieve different conformation-related functions.