Coarse‐Grained Simulations of Transitions in the E2‐to‐E1 Conformations for Ca ATPase (SERCA) Show Entropy–Enthalpy Compensation

Nagarajan, Anu; Andersen, Jens Peter; Woolf, Thomas B.

doi:10.1016/j.jmb.2012.06.001

Cited by 14 publications

(15 citation statements)

References 52 publications

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“…These studies provided key predictions on Ca 2+ binding and allosteric coupling of domain dynamics, but the time scales used in the atomistic simulations were too short for Ca 2+ -free E1 to populate a fully relaxed E1 intermediate state [12], [13]. Coarse-grained simulations were used to simulate the transition path between E2 and E1, but that study did not take into consideration important atomistic factors, such as changes in protonation states of the Ca 2+ -binding sites and the explicit inclusion of metal ions [14].…”

Section: Introductionmentioning

confidence: 99%

Microsecond Molecular Dynamics Simulations of Mg2+- and K+- Bound E1 Intermediate States of the Calcium Pump

2014

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We have performed microsecond molecular dynamics (MD) simulations to characterize the structural dynamics of cation-bound E1 intermediate states of the calcium pump (sarcoendoplasmic reticulum Ca2+-ATPase, SERCA) in atomic detail, including a lipid bilayer with aqueous solution on both sides. X-ray crystallography with 40 mM Mg2+ in the absence of Ca2+ has shown that SERCA adopts an E1 structure with transmembrane Ca2+-binding sites I and II exposed to the cytosol, stabilized by a single Mg2+ bound to a hybrid binding site I′. This Mg2+-bound E1 intermediate state, designated E1•Mg2+, is proposed to constitute a functional SERCA intermediate that catalyzes the transition from E2 to E1•2Ca2+ by facilitating H+/Ca2+ exchange. To test this hypothesis, we performed two independent MD simulations based on the E1•Mg2+ crystal structure, starting in the presence or absence of initially-bound Mg2+. Both simulations were performed for 1 µs in a solution containing 100 mM K+ and 5 mM Mg2+ in the absence of Ca2+, mimicking muscle cytosol during relaxation. In the presence of initially-bound Mg2+, SERCA site I′ maintained Mg2+ binding during the entire MD trajectory, and the cytosolic headpiece maintained a semi-open structure. In the absence of initially-bound Mg2+, two K+ ions rapidly bound to sites I and I′ and stayed loosely bound during most of the simulation, while the cytosolic headpiece shifted gradually to a more open structure. Thus MD simulations predict that both E1•Mg2+ and E•2K+ intermediate states of SERCA are populated in solution in the absence of Ca2+, with the more open 2K+-bound state being more abundant at physiological ion concentrations. We propose that the E1•2K+ state acts as a functional intermediate that facilitates the E2 to E1•2Ca2+ transition through two mechanisms: by pre-organizing transport sites for Ca2+ binding, and by partially opening the cytosolic headpiece prior to Ca2+ activation of nucleotide binding.

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Section: Introductionmentioning

confidence: 99%

Microsecond Molecular Dynamics Simulations of Mg2+- and K+- Bound E1 Intermediate States of the Calcium Pump

2014

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“…The subsequent X‐ray crystal structures cover almost all the conformations at different physiological states in the E1/E2 reaction cycle and demonstrate large‐scale domain movements of the cytoplasm domains coupled with the rearrangement of transmembrane helices. The large conformational changes on the reaction cycle have been investigated by theoretical studies like normal mode analysis, atomistic and coarse‐grained molecular dynamics (MD) simulations, and principal component analysis (PCA) . This is an appropriate target to examine the applicability of MT to complex motions in membrane proteins.…”

Section: Introductionmentioning

confidence: 99%

Hierarchical domain‐motion analysis of conformational changes in sarcoplasmic reticulum Ca²⁺‐ATPase

et al. 2015

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Sarco(endo)plasmic reticulum Ca(2+)-ATPase transports two Ca(2+) per ATP-hydrolyzed across biological membranes against a large concentration gradient by undergoing large conformational changes. Structural studies with X-ray crystallography revealed functional roles of coupled motions between the cytoplasmic domains and the transmembrane helices in individual reaction steps. Here, we employed "Motion Tree (MT)," a tree diagram that describes a conformational change between two structures, and applied it to representative Ca(2+) -ATPase structures. MT provides information of coupled rigid-body motions of the ATPase in individual reaction steps. Fourteen rigid structural units, "common rigid domains (CRDs)" are identified from seven MTs throughout the whole enzymatic reaction cycle. CRDs likely act as not only the structural units, but also the functional units. Some of the functional importance has been newly revealed by the analysis. Stability of each CRD is examined on the morphing trajectories that cover seven conformational transitions. We confirmed that the large conformational changes are realized by the motions only in the flexible regions that connect CRDs. The Ca(2+) -ATPase efficiently utilizes its intrinsic flexibility and rigidity to response different switches like ligand binding/dissociation or ATP hydrolysis. The analysis detects functional motions without extensive biological knowledge of experts, suggesting its general applicability to domain movements in other membrane proteins to deepen the understanding of protein structure and function.

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“…While experimental techniques have provided much of the available structural information, computer simulations of biological systems and of membrane proteins in particular have been able to provide critical information about the dynamics and energetics of these macromolecules. 4–6 …”

Section: Introductionmentioning

confidence: 99%

Dynamic Heterogeneous Dielectric Generalized Born (DHDGB): An Implicit Membrane Model with a Dynamically Varying Bilayer Thickness

Panahi

Feig

2013

J. Chem. Theory Comput.

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An extension to the heterogeneous dielectric generalized Born (HDGB) implicit membrane formalism is presented to allow dynamic membrane deformations in response to membrane-inserted biomolecules during molecular dynamic simulations. The flexible membrane is implemented through additional degrees of freedom that represent the membrane deformation at the contact points of a membrane-inserted solute with the membrane. The extra degrees of freedom determine the dielectric and non-polar solvation free energy profiles that are used to obtain the solvation free energy in the presence of the membrane and are used to calculate membrane deformation free energies according to an elastic membrane model. With the dynamic HDGB (DHDGB) model the membrane is able to deform in response to the insertion of charged molecules thereby avoiding the overestimation of insertion free energies with static membrane models. The DHDGB model also allows the membrane to respond to the insertion of membrane-spanning solutes with hydrophobic mismatch. The model is tested with the membrane insertion of amino acid side chain analogs, arginine-containing helices, the WALP23 peptide, and the gramicidin A channel.

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Coarse‐Grained Simulations of Transitions in the E2‐to‐E1 Conformations for Ca ATPase (SERCA) Show Entropy–Enthalpy Compensation

Cited by 14 publications

References 52 publications

Microsecond Molecular Dynamics Simulations of Mg2+- and K+- Bound E1 Intermediate States of the Calcium Pump

Microsecond Molecular Dynamics Simulations of Mg2+- and K+- Bound E1 Intermediate States of the Calcium Pump

Hierarchical domain‐motion analysis of conformational changes in sarcoplasmic reticulum Ca²⁺‐ATPase

Dynamic Heterogeneous Dielectric Generalized Born (DHDGB): An Implicit Membrane Model with a Dynamically Varying Bilayer Thickness

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Coarse‐Grained Simulations of Transitions in the E2‐to‐E1 Conformations for Ca ATPase (SERCA) Show Entropy–Enthalpy Compensation

Cited by 14 publications

References 52 publications

Microsecond Molecular Dynamics Simulations of Mg2+- and K+- Bound E1 Intermediate States of the Calcium Pump

Microsecond Molecular Dynamics Simulations of Mg2+- and K+- Bound E1 Intermediate States of the Calcium Pump

Hierarchical domain‐motion analysis of conformational changes in sarcoplasmic reticulum Ca2+‐ATPase

Dynamic Heterogeneous Dielectric Generalized Born (DHDGB): An Implicit Membrane Model with a Dynamically Varying Bilayer Thickness

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Hierarchical domain‐motion analysis of conformational changes in sarcoplasmic reticulum Ca²⁺‐ATPase