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Structural Transition States Explored With Minimalist Coarse Grained Models: Applications to Calmodulin
Transitions between different conformational states are ubiquitous in proteins, being
involved in signaling, catalysis, and other fundamental activities in cells. However,
modeling those processes is extremely difficult, due to the need of efficiently exploring
a vast conformational space in order to seek for the actual transition path for systems
whose complexity is already high in the stable states. Here we report a strategy that
simplifies this task attacking the complexity on several sides. We first apply a minimalist
coarse-grained model to Calmodulin, based on an empirical force field with a partial
structural bias, to explore the transition paths between the apo-closed state and the
Ca-bound open state of the protein. We then select representative structures along the
trajectory based on a structural clustering algorithm and build a cleaned-up trajectory
with them. We finally compare this trajectory with that produced by the online tool
MinActionPath, by minimizing the action integral using a harmonic network model,
and with that obtained by the PROMPT morphing method, based on an optimal
mass transportation-type approach including physical constraints. The comparison is
performed both on the structural and energetic level, using the coarse-grained and the
atomistic force fields upon reconstruction. Our analysis indicates that this method returns
trajectories capable of exploring intermediate states with physical meaning, retaining a
very low computational cost, which can allow systematic and extensive exploration of
the multi-stable proteins transition pathways.