Coupling of conformational switches in calcium sensor unraveled with local Markov models and transfer entropy

Proteins often have multiple switching domains that are coupled to each other and to binding of ligands in order to realize signaling functions. Here we investigate the C2A domain of Synaptotagmin-1 (Syt-1), a calcium sensor in the neurotransmitter release machinery and a model system for the large family of C2 membrane binding domains. We combine extensive molecular dynamics (MD) simulations and Markov modeling in order to model conformational switching domains, their states and their dependence on bound calcium ions. Using transfer entropy, we characterize how the switching domains are coupled via directed or allosteric mechanisms and give rise to the calcium sensing function of the protein. Our switching mechanism contributes to the understanding of the neurotransmitter release machinery and the proposed methodological approach serves as a template to analyze conformational switching domains and study their coupling in macromolecular machines in general.