  The flexibility in the structure of calmodulin (CaM) allows its binding to
over 300 target proteins in the cell. To investigate the structure-function
relationship of CaM, we combined methods of computer simulation and experiments
based on circular dichroism (CD) to investigate the structural characteristics
of CaM that influence its target recognition in crowded cell-like conditions.
We developed a unique multiscale solution of charges computed from quantum
chemistry, together with protein reconstruction, coarse-grained molecular
simulations, and statistical physics, to represent the charge distribution in
the transition from apoCaM to holoCaM upon calcium binding. Computationally, we
found that increased levels of macromolecular crowding, in addition to calcium
binding and ionic strength typical of that found inside cells, can impact the
conformation, helicity and the EF hand orientation of CaM. Because EF hand
orientation impacts the affinity of calcium binding and the specificity of
CaM's target selection, our results may provide unique insight into
understanding the promiscuous behavior of calmodulin in target selection inside
cells.
