Cells must signal to adapt to a changing environment. Calcium (Ca²⁺) signaling requires Ca²⁺ as a messenger whose concentration varies with time. Calmodulin (CaM) is an evolutionarily conserved Ca²⁺-binding protein for decoding the Ca²⁺ signal in all eukaryotic cells, which selectively activates distinctive targets in downstream pathways. However, its Ca²⁺-binding properties alone appear insufficient to decode rapidly fluctuating Ca²⁺ signals. We are testing the hypothesis that the interaction between CaM and its targets directly tunes the Ca²⁺-binding properties of CaM through reciprocal interactions mediated by conformational adjustments. We apply methods of quantum mechanics, statistical physics, physical modeling, and machine learning to understand the molecular mechanism of target binding and selection in CaM-dependent Ca²⁺ signaling pathways. We are currently interested in developing force fields for calcium ions and coarse-grained models for CaM and its binding targets. We show that the conformations of CaM and its target must both undergo gross structural changes to form a bound complex. The structural variation of a bound complex depends on the feature of a target that influences the stability of Ca²⁺ -binding loops. This binary complex reveals unique binding affinity for Ca²⁺ which does not exist in CaM alone.