University of Kentucky

Poster Title

Understanding Ion Binding Affinity and Selectivity in Beta Parvalbumin Using Molecular Dynamics and Mean Sphere Approximation Theory

Institution

University of Kentucky

Abstract

Parvalbumin (PV) is a globular calcium-binding protein expressed primarily in skeletal muscle and secondarily in neuronal tissue. Defects in PV function have been correlated with a variety of severe pathological conditions, including epileptic seizures, while engineered sequences have been shown to mitigate cardiac dysfunction in animal models. Our computational studies of the beta PV isoform seek to quantify thermodynamic drivers of high affinity and selective calcium (Ca2+) binding at the pseudo and canonical EF structural motifs. Specifically, we employed molecular dynamics (MD) simulations and Mean Sphere Approximation (MSA) theory to quantify the structural and thermodynamic factors favoring Ca2+-binding relative to other common intracellular electrolytes in both EF-hands. Our MD simulations provided the coordination geometry and the density of metal-chelating oxygens within the EF-hand scaolds for both calcium and magnesium. These structural data inform the MSA model, from which the free energy and chemical potential within the metal binding site are predicted. This approach provided a thermodynamic basis for ion affinity and selectivity in beta-PV over a broad range of electrolyte compositions and concentrations that would be difficult to ascertain by MD alone. The minimal computational cost of MSA theory relative to MD further offers the potential to predict key thermodynamics quantities across a wide range of PV sequence homologs and Ca2+- binding proteins.

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Understanding Ion Binding Affinity and Selectivity in Beta Parvalbumin Using Molecular Dynamics and Mean Sphere Approximation Theory

Parvalbumin (PV) is a globular calcium-binding protein expressed primarily in skeletal muscle and secondarily in neuronal tissue. Defects in PV function have been correlated with a variety of severe pathological conditions, including epileptic seizures, while engineered sequences have been shown to mitigate cardiac dysfunction in animal models. Our computational studies of the beta PV isoform seek to quantify thermodynamic drivers of high affinity and selective calcium (Ca2+) binding at the pseudo and canonical EF structural motifs. Specifically, we employed molecular dynamics (MD) simulations and Mean Sphere Approximation (MSA) theory to quantify the structural and thermodynamic factors favoring Ca2+-binding relative to other common intracellular electrolytes in both EF-hands. Our MD simulations provided the coordination geometry and the density of metal-chelating oxygens within the EF-hand scaolds for both calcium and magnesium. These structural data inform the MSA model, from which the free energy and chemical potential within the metal binding site are predicted. This approach provided a thermodynamic basis for ion affinity and selectivity in beta-PV over a broad range of electrolyte compositions and concentrations that would be difficult to ascertain by MD alone. The minimal computational cost of MSA theory relative to MD further offers the potential to predict key thermodynamics quantities across a wide range of PV sequence homologs and Ca2+- binding proteins.