Calmodulin: calcium, potassium, and magnesium ion multiple equilibria and kinetics for interconversion, including the effect of repeated stimulation

Using computer simulations, with realistic values for the intrinsic thermodynamic binding constants and kinetic on and off rate constants at the four metal-binding sites, the calmodulin molecule is shown to have been optimally adjusted by evolution for biological function. Despite a very large number of potential molecular states, depending upon occupation by potassium, calcium, or magnesium ions, the system restricts itself to a small number of physiologically-significant equilibrium species. It appears to possess built-in triggers for biological processes, with rapid (approximately 20 ms time-scale), step-function shaped, changes of the populations of the CMKK, CMMK, CKKK, CMMM (and CCKK) states. The time-response of calmodulin to periodic changes in ionic levels (2 and 5 s-1) makes it quite adequate for repeated stimulations. In short, calmodulin appears as a very selective information transmitter at the molecular level.