Abstract
Calmodulin (CaM) is a ubiquitous Ca2+ sensor and a crucial signalling hub in many pathways aberrantly activated in disease. However, the mechanistic basis of its ability to bind diverse signalling molecules including G-protein-coupled receptors, ion channels and kinases remains poorly understood. Here we harness the high resolution of molecular dynamics simulations and the analytical power of Markov state models to dissect the molecular underpinnings of CaM binding diversity. Our computational model indicates that in the absence of Ca2+, sub-states in the folded ensemble of CaM's C-terminal domain present chemically and sterically distinct topologies that may facilitate conformational selection. Furthermore, we find that local unfolding is off-pathway for the exchange process relevant for peptide binding, in contrast to prior hypotheses that unfolding might account for binding diversity. Finally, our model predicts a novel binding interface that is well-populated in the Ca2+-bound regime and, thus, a candidate for pharmacological intervention.
Highlights
Calmodulin (CaM) is a ubiquitous Ca2 þ sensor and a crucial signalling hub in many pathways aberrantly activated in disease
In addition to repositioning of the residues that ligate the Ca2 þ ions in each of the Ca2 þ -binding sites (Fig. 1b,c), Ca2 þ binding is accompanied by reorientation of the EF hand a-helices to achieve a more compact clustering of the four aromatic residues in the C-lobe of CaM (C-CaM) hydrophobic core (Fig. 1d,e)
Molecular dynamics (MD) simulations allowed us to bridge this gap, preserving the atomic-level detail afforded by high-resolution structures while providing extensive kinetic information that can be unified and interpreted through the framework of Markov state models (MSMs)
Summary
Calmodulin (CaM) is a ubiquitous Ca2 þ sensor and a crucial signalling hub in many pathways aberrantly activated in disease. Comparison of high-resolution structures of apo (Ca2 þ unbound) and holo (Ca2 þ -bound) CaM clarified the functional role of these dynamics by indicating that Ca2 þ binding induces large-scale structural rearrangements that expose each lobe’s hydrophobic interface to CaM-binding partners[6,10] (Fig. 1). These binding partners commonly feature a pair of bulky hydrophobic residues that serve as anchors to the hydrophobic interface presented by each lobe of Ca2 þ -bound CaM, which can accommodate variable spacing between these anchor residues due to the flexibility of the inter-lobe linker[11]. Only the question of Ca2 þ -binding has been addressed, while the structural basis underlying CaM’s ability to interact with a diverse set of binding partners has not been broached computationally
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