Allostery is referred to as the “second secret of life” and yet the molecular-level mechanisms underlying this phenomenon remain enigmatic.  Liver pyruvate kinase (LPYK) is an important enzyme that is involved in the last step in glycolysis and is model K-type allosteric enzyme.  The binding of fructose 1,6-bisphosphate (FBP) to LPYK allosterically enhances the binding affinity of the enzyme to phosphoenolpyruvate (PEP), the natural substrate of the enzyme.  Additionally, the binding of alanine to a third pocket allosterically reduces the binding affinity of LPYK to PEP.  This behavior has been well characterized using slew of experimental techniques including an alanine mutagenesis scan of the entire protein.  Here, we will demonstrate how using extensive all-atom molecular dynamics simulations of the four relevant substrate states coupled with recently developed allosteric analyses yields predictions that correlate well with experimental mutagenesis data.  We identify novel allosteric paths and sensitivity points that help explain the molecular-level mechanisms of allosteric enhancement and inhibition.  Ultimately, these results demonstrate the importance of considering the full thermodynamic picture of an enzyme to make predictions on allostery and allosteric paths.

A complete thermodynamic picture of allosteric activation and inhibition in liver pyruvate kinase

ACS Fall 2021

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