Thermodynamics of Cation Binding to the Sarcoendoplasmic Reticulum Calcium ATPase Pump and Impacts on Enzyme Function

Journal of Chemical Theory and Computation
Bin SunPeter M Kekenes-Huskey

Abstract

Sarcoendoplasmic reticulum Ca2+-ATPase (SERCA) is a transmembrane pump that plays an important role in transporting calcium into the sarcoplasmic reticulum (SR). While calcium (Ca2+) binds SERCA with micromolar affinity, magnesium (Mg2+) and potassium (K+) also compete with Ca2+ binding. However, the molecular bases for these competing ions' influence on the SERCA function and the selectivity of the pump for Ca2+ are not well-established. We therefore used in silico methods to resolve molecular determinants of cation binding in the canonical site I and II Ca2+ binding sites via (1) triplicate molecular dynamics (MD) simulations of Mg2+, Ca2+, and K+-bound SERCA, (2) mean spherical approximation (MSA) theory to score the affinity and selectivity of cation binding to the MD-resolved structures, and (3) state models of SERCA turnover informed from MSA-derived affinity data. Our key findings are that (a) coordination at sites I and II is optimized for Ca2+ and to a lesser extent for Mg2+ and K+, as determined by MD-derived cation-amino acid oxygen and bound water configurations, (b) the impaired coordination and high desolvation cost for Mg2+ precludes favorable Mg2+ binding relative to Ca2+, while K+ has limited capacity to bind s...Continue Reading

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Citations

Jun 26, 2020·PLoS Computational Biology·Hadi RahmaninejadPeter Kekenes-Huskey
Jun 14, 2020·International Journal of Molecular Sciences·Rodrigo Aguayo-Ortiz, L Michel Espinoza-Fonseca
Apr 8, 2020·Computational and Structural Biotechnology Journal·Eli Fernández-de GortariL Michel Espinoza-Fonseca
Mar 10, 2021·The Journal of Chemical Physics·Anh Phan, Alberto Striolo
Apr 4, 2021·International Journal of Molecular Sciences·L Michel Espinoza-Fonseca
Oct 19, 2020·Biophysical Journal·Olga N RaguimovaL Michel Espinoza-Fonseca
Jun 12, 2021·The Journal of Physical Chemistry. B·Kalyan ImmadisettyPeter M Kekenes-Huskey

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