The protein CyaA is an important virulence factor of Bordetella pertussis involved in the whooping cough disease. The AC domain of CyaA is activated in eukaryotic host cells as an adenyl-cyclase by the ubiquitous and calcium sensitive protein calmodulin (CaM). This activation transformes the ATP into cAMP in an uncontrolled way, leading to severe cellular dysfunction. Only the structure of AC complexed with calcium-loaded calmodulin has been resolved by X-ray crystallography. Starting from this structure, molecular dynamics simulations of AC free and in complex with calmodulin enabled to characterize the effect of the calmodulin and calcium ions on the conformational plasticity of the complex. Conformational tendencies of free AC were also studied. The joint analysis of energetic influences and hydrogen bonds revealed a network of interactions between AC and calmodulin, in which three key residues, that may play an allosteric role on the catalytic activity of the adenyl-cyclase, were modified by site-directed mutagenesis. These experimental tests have led to the identification of an allosteric region which assures the communication of the conformational transition information between the binding site of the calmodulin and the catalytic site. A more thorough conformational exploration of the unbound AC state was undertaken by an innovative temperature accelerated molecular dynamics (TAMD) method. It led to a prediction of some sampled conformations of AC in its unbound state. These predictions could be used in the future to stabilize the free state and to facilitate the experimental study of its structure
