Coarse-Grained Modeling and Molecular Dynamics Simulations of Ca²⁺-Calmodulin

Calmodulin (CaM) is a calcium-binding protein that transduces signals to downstream proteins through target binding upon calcium binding in a time-dependent manner. Understanding the target binding process that tunes CaM's affinity for the calcium ions (Ca²⁺), or vice versa, may provide insight into how Ca²⁺-CaM selects its target binding proteins. However, modeling of Ca²⁺-CaM in molecular simulations is challenging because of the gross structural changes in its central linker regions while the two lobes are relatively rigid due to tight binding of the Ca²⁺ to the calcium-binding loops where the loop forms a pentagonal bipyramidal coordination geometry with Ca²⁺. This feature that underlies the reciprocal relation between Ca²⁺ binding and target binding of CaM, however, has yet to be considered in the structural modeling. Here, we presented a coarse-grained model based on the Associative memory, Water mediated, Structure, and Energy Model (AWSEM) protein force field, to investigate the salient features of CaM. Particularly, we optimized the force field of CaM and that of Ca²⁺ ions by using its coordination chemistry in the calcium-binding loops to match with experimental observations. We presented a "community model" of CaM that is capable of sampling various conformations of CaM, incorporating various calcium-binding states, and carrying the memory of binding with various targets, which sets the foundation of the reciprocal relation of target binding and Ca²⁺ binding in future studies.