Protein-ligand interactions play a central role in many biological functions and in the development. These interactions take place within and modulate the dynamic conformational ensemble of a protein. By integrating long-timescale all-atom molecular dynamics simulations with Markov state models we have elucidate the conformational ensembles of PKA’s cyclic-nucleotide binding domain A for the cAMP-free (apo) and cAMP-bound states. These models provide significant insight into the mechanisms of allostery in the cyclic-nucleotide binding domain. We show that the system exhibits a shallow free energy landscapes that links functional states through multiple transition pathways, supporting conformational selection as the general mechanism of allostery in this canonical signaling domain. The models also illuminate the dynamic nature of protein-ligand interactions, show the transient nature of many of the key interactions between the cAMP and the cyclic-nucleotide binding domain.

Protein-ligand interactions through the computational microscope: Allostery in a canonical signaling domain

251st National Meeting (2016)

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