University of Kentucky
Molecular Dynamics Studies of Calcium Binding to Beta Parvalbumin
Institution
University of Kentucky
Faculty Advisor/ Mentor
Peter Kekenes-Huskey
Abstract
Parvalbumin (PV) is a globular calcium-binding protein expressed primarily in skeletal muscle and secondarily in neuronal tissue. While defects in PV function have been correlated with a variety of severe pathological conditions, including epileptic seizures, engineered sequences have been shown to mitigate cardiac dysfunction in animal models, which could potentially benefit heart patients in Kentucky and the United States. Our computational studies of the beta PV isoform seek to understand calcium binding at the protein’s pseudo and canonical "EF" hand secondary structures. Specifically, we have employed molecular dynamics (MD) simulations to understand why calcium binds tightly in wild-type PV and even more tightly upon mutating an amino acid (Leucine-85-Phenylalanine) far from the calcium binding sites. Our MD simulations were analyzed to reveal changes in PV’s three dimensional structure, including alpha helical angles and interhelical distances, as well as their influence on the density of protein oxygens that directly bind calcium. These data may provide a thermodynamic basis for how mutations vary calcium affinity and more importantly, could guide re-engineering of PV to mitigate defective calcium signaling in heart cells. Broadly speaking, since the EF hand is common to a large class of proteins, we anticipate that our findings could shed light on related calcium-dependent proteins that modulate a wide range of physiological functions.
Molecular Dynamics Studies of Calcium Binding to Beta Parvalbumin
Parvalbumin (PV) is a globular calcium-binding protein expressed primarily in skeletal muscle and secondarily in neuronal tissue. While defects in PV function have been correlated with a variety of severe pathological conditions, including epileptic seizures, engineered sequences have been shown to mitigate cardiac dysfunction in animal models, which could potentially benefit heart patients in Kentucky and the United States. Our computational studies of the beta PV isoform seek to understand calcium binding at the protein’s pseudo and canonical "EF" hand secondary structures. Specifically, we have employed molecular dynamics (MD) simulations to understand why calcium binds tightly in wild-type PV and even more tightly upon mutating an amino acid (Leucine-85-Phenylalanine) far from the calcium binding sites. Our MD simulations were analyzed to reveal changes in PV’s three dimensional structure, including alpha helical angles and interhelical distances, as well as their influence on the density of protein oxygens that directly bind calcium. These data may provide a thermodynamic basis for how mutations vary calcium affinity and more importantly, could guide re-engineering of PV to mitigate defective calcium signaling in heart cells. Broadly speaking, since the EF hand is common to a large class of proteins, we anticipate that our findings could shed light on related calcium-dependent proteins that modulate a wide range of physiological functions.