ct0c00043_si_001.pdf (4.92 MB)
Coupling of Conformational Switches in Calcium Sensor Unraveled with Local Markov Models and Transfer Entropy
journal contribution
posted on 2020-03-31, 18:12 authored by Tim Hempel, Nuria Plattner, Frank NoéProteins often have multiple switching
domains that are coupled
to each other and to the 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 with Markov modeling
in order to model conformational switching domains, their states,
and their dependence on bound calcium ions. Then, we use transfer
entropy to characterize how the switching domains are coupled via
directed or allosteric mechanisms and give rise to the calcium sensing
function of the protein. Our proposed switching mechanism contributes
to the understanding of the neurotransmitter release machinery. Furthermore,
the methodological approach we develop serves as a template to analyze
conformational switching domains and the broad study of their coupling
in macromolecular machines.