Background: Hyperpolarization-activated cyclic nucleotide-modulated (HCN) ion channels control rhythmicity in neurons and cardiomyocytes, but their regulatory mechanism is not fully understood. Results: Both tetramerization and cAMP binding reduce dynamics in the HCN intracellular region. Conclusion: Intracellular HCN dynamics are crucial for HCN autoinhibition and cAMP modulation. Significance: A full map of the changes in dynamics coupled to HCN gating is necessary to understand HCN regulation by cAMP.
The conformational sampling of monomeric, membrane-bound phospholamban is described from computer simulations. Phospholamban (PLB) plays a key role as a regulator of sarcoplasmic reticulum calcium ATPase. An implicit membrane model is used in conjunction with replica exchange molecular dynamics simulations to reach mus-ms timescales. The implicit membrane model was also used to study the effect of different membrane thicknesses by scaling the low-dielectric region. The conformational sampling with the membrane model mimicking dipalmitoylphosphatidylcholine bilayers is in good agreement overall with experimental measurements, but consists of a wide variety of different conformations including structures not described previously. The conformational ensemble shifts significantly in the presence of thinner or thicker membranes. This has implications for the structure and dynamics of PLB in physiological membranes and offers what we believe to be a new interpretation of previous experimental measurements of PLB in detergents and microsomal membrane.
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The Heterogeneous Dielectric Generalized Born (HDGB) implicit membrane formalism is extended by the addition of a van der Waals dispersion term to better describe the nonpolar components of the free energy of solvation. The new model, termed HDGBvdW, improves the energy estimates in the hydrophobic interior of the membrane, where polar and charged species are rarely found and non-polar interactions become significant. The implicit van der Waals term for the membrane environment extends the model from Gallicchio et al. (J. Comp. Chem. (2004) 25, 479-499) by combining separate contributions from each of the membrane components. The HDGBvdW model is validated with a series of test cases ranging from membrane insertion and pair association profiles of amino acid side chain analogs and transmembrane helices. Overall, the HDGBvdW model leads to increased agreement with explicit membrane simulation results and experimental data.
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