Key result
Molecular dynamics and thermodynamic modeling demonstrated that SERCA binding sites are optimized for Ca2+ coordination, while Mg2+ acts as an inhibitor and K+ as an intermediate.
Why the study?
Although Mg2+ and K+ compete with Ca2+ binding to SERCA, the molecular bases for these competing ions' influence on SERCA function had not been established.
This computational study provides a quantitative thermodynamic basis for SERCA function, explaining its selectivity for Ca2+ over Mg2+ and K+.
May inform SERCA ion selectivity models; leaves open validation and therapeutic relevance in human heart failure.
Sarcoendoplasmic reticulum Ca2+-ATPase (SERCA) is a transmembrane pump that plays an important role in transporting calcium into the sarcoplasmic reticulum (SR). While Ca2+ binds SERCA with micromolar affinity, Mg2+ and K+ compete with Ca2+ binding, yet the molecular bases for these competing ions' influence on SERCA function has not been established. We therefore used three in silico methods to resolve molecular determinants of cation binding in the canonical site I and II Ca2+ binding sites: 1) triplicate molecular dynamic (MD) simulations of Mg2+, Ca2+ and K+-bound SERCA. 2) mean spherical approximation (MSA) theory to determine 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 are 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 site I, c) Mg2+ most likely acts as inhibitor and K+ as intermediate in SERCA's reaction cycle, based on a state model of SERCA turnover. These findings provide a quantitative basis for SERCA function that leverages molecular-scale thermodynamic data and rationalize enzyme activity across broad range of K+, Ca2+ and Mg2+ concentrations.
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Sun et al. (2018) studied Cation binding to SERCA. Ca2+, Mg2+, and K+ binding to SERCA was evaluated on Cation coordination and binding chemical potentials. Molecular dynamics and thermodynamic modeling demonstrated that SERCA binding sites are optimized for Ca2+ coordination, while Mg2+ acts as an inhibitor and K+ as an intermediate.
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