Ligand-induced protein allostery plays a central role in modulating cellular signaling pathways, yet understanding allosteric mechanisms remains challenging. A prototypical example is the canonical and ubiquitous intracellular signal transduction cyclic-nucleotide binding domain. In this talk, I will discuss the conserved cyclic-nucleotide binding domain of protein kinase A’s (PKA) regulatory subunit, which is a prototype signaling unit, and our efforts to combine long-timescale all-atom molecular dynamics simulations with Markov state models to elucidate the conformational ensembles of PKA’s cyclic-nucleotide binding domain A for cAMP-free and cAMP-bound states. We find that the both systems exhibit shallow free energy landscapes that share a majority of their conformational states and that transitions across the free energy landscape do not follow a single dominant pathway. Collectively, our methods expose the allosteric mechanism at a detail beyond which is accessible to current experimental techniques. Our results support conformational selection as the principle mechanism of allostery in this canonical signaling domain.

Elucidating protein function and dynamics through molecular simulations and Markov state modeling: Allostery through conformational selection

249th National Meeting (2015)

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