On the Selective Promiscuity of Calmodulin: a computational study

Abstract: Calmodulin (CaM) is a calcium sensing protein that regulates a wide variety of cellular function. CaM has the ability to bind more than 300 different target peptides in a Ca2+-dependent manner, mainly through the exposure of hydrophobic residues. How CaM can bind a large number of targets while retaining some aspects of selectivity is a fascinating open question.
Here, we explore the mechanism of CaM selective promiscuity for selected target membrane proteins. Analyzing enhanced sampling molecular dynamics simulations of Ca2+-bound and Ca2+-free CaM via spectral clustering has allowed us to identify distinct conformational states, characterized by inter-residue contacts and by the solvent exposure of specific CaM residues. By comparing those to the residues involved in binding to 10 different target peptides (in a total of 25 different structures), we have identified CaM conformational states that define specific binding classes: shallow, intermediate and deep. This analysis has further revealed that binding to the C-terminal lobe of CaM appears more selective and involves specific conformational states, while binding to the N-terminal lobe of CaM happens through a more flexible mechanism.
This work furthers our understanding of the mechanism of CaM binding and selectivity to different target membrane proteins and paves the way towards a comprehensive model of CaM selectivity.