Calcium binding and allosteric signaling mechanisms for the sarcoplasmic reticulum Ca²⁺ ATPase

Abstract

The sarcoplasmic reticulum Ca 21 ATPase (SERCA) is a membrane-bound pump that utilizes ATP to drive calcium ions from the myocyte cytosol against the higher calcium concentration in the sarcoplasmic reticulum. Conformational transitions associated with Ca 21 -binding are important to its catalytic function. We have identified collective motions that partition SERCA crystallographic structures into multiple catalytically-distinct states using principal component analysis. Using Brownian dynamics simulations, we demonstrate the important contribution of surface-exposed, polar residues in the diffusional encounter of Ca 21 . Molecular dynamics simulations indicate the role of Glu309 gating in binding Ca 21 , as well as subsequent changes in the dynamics of SERCA's cytosolic domains. Together these data provide structural and dynamical insights into a multistep process involving Ca 21 binding and catalytic transitions.

Finite-element estimation of protein–ligand association rates with post-encounter effects: applications to calcium binding in troponin C and SERCA

“…1b) has been suggested as a predominant entryway for Ca 2+ binding based on molecular dynamics (MD) and solutions of the Poisson Boltzmann equation. For SERCA, we consider association rates to the L3 recognition domain discussed in [26]. This recognition domain is lined with several negatively-charged amino acids, including Glu51, Glu55, Glu58, Asp59 and Asp 109, which contribute to a strongly negative electrostatic potential favoring cation association.…”

“…Since the purpose of this study is to illustrate the incorporation of estimated PMF data into a numerical model, we are utilizing data from molecular dynamics studies of Troponin C ( in preparation ) and SERCA [26] for this experiment. In these studies, the PMF along the reaction coordinate was computed using Adaptive Force Biasing [14] and Weighted Histogram Analysis Method [17], respectively, and details of the windows and convergence are described in our manuscripts.…”

Prediction and validation of protein intermediate states from structurally rich ensembles and coarse-grained simulations

“…For example, McCammon and co-workers121314 showed the utility of PCs obtained from X-ray structural ensembles as CVs to track MD; a recent work used PCs to estimate free-energies of transitions15. Here we build on the idea to use the two dominant PCs as complex multidimensional reaction coordinates to reveal the direction of ensemble-encoded conformational changes.…”

Computational modeling of subcellular transport and signaling

“…Several approaches have incorporated finite-volume, diffusing particles in the simulation of proteins through Brownian dynamics (BD) methods. Recent examples include BD predictions of diffusion-limited Ca 2+ binding to TnC [45, 46] and SERCA [47], as well as current-voltage relationships for K + diffusion through the inwardly-rectifying potassium channel [48]. Given the computational expense of explicit particle simulations, efforts to combine continuum and discrete simulations could potentially offer the best of both worlds, see for example Bauler et al [49].…”