Understanding Ion Binding Affinity and Selectivity in beta-Parvalbumin Using Molecular Dynamics and Mean Spherical Approximation Theory

作者：Kucharski Amir N^*; Scott Caitlin E^*; Davis Jonathan P; Kekenes Huskey Peter M

来源：Journal of Physical Chemistry B, 2016, 120(33): 8617-8630.

DOI：10.1021/acs.jpcb.6b02666

Parvalbumin (PV) is a globular calcium (Ca2+)selective protein expressed in a variety of biological tissues. Our computational studies of the rat beta-parvalbumin (beta-PV) isoform seek to elucidate the molecular thermodynamics of Ca2+ versus magnesium (Mg2+) binding at the protein's two EF-hand motifs. Specifically, we have utilized molecular dynamics (MD) simulations and a mean-field electrolyte model (mean spherical approximation (MSA) theory) to delineate how the EF-hand scaffold controls the "local" thermodynamics of Ca2+ binding selectivity over Mg2+. Our MD simulations provide the probability density of metalchelating oxygens within the EF-hand scaffolds for both Ca2+ and Mg2+, as well the conformational strain induced by Mg2+ relative to Ca2+ binding. MSA theory utilizes the binding domain oxygen and charge distributions to predict the chemical potential of ion binding, as well as their corresponding concentrations within the binding domain. We find that the electrostatic and steric contributions toward ion binding were similar for Mg2+ and Ca2+, yet the latter was 5.5 kcal/mol lower in enthalpy When internal strain within the EF hand, was considered. We therefore speculate that beyond differences in dehydration energies for the Ca2+ versus Mg2+, strain induced in the beta-PV EF hand by cation binding significantly contributes to the nearly 10,000 -fold difference in binding affinity reported in the literature. We further complemented our analyses of local factors governing cation binding selectivity with whole-protein (global) contributions, such as interhelical residue residue contacts and solvent exposure of hydrophobic surface. These contributions were found to be comparable for both Ca2+ and Mg2+-bound beta-PV, which may implicate local factors, EF-hand strain, and dehydration, in, providing the primary means of selectivity. We anticipate these methods could be used to estimate metal binding thermodynamics across a broad range of PV sequence homologues and EF-hand-containing, Ca2+ binding proteins.

• 出版日期2016-8-25