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Cholesterol driven alteration of the conformation and dynamics of phospholamban in model membranes

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Cholesterol driven alteration of the conformation and dynamics of phospholamban in model membranes. / Manna, Moutusi; Mukhopadhyay, Chaitali.

In: Physical Chemistry Chemical Physics, Vol. 13, No. 45, 07.12.2011, p. 20188-20198.

Research output: Contribution to journalArticleScientificpeer-review

Harvard

Manna, M & Mukhopadhyay, C 2011, 'Cholesterol driven alteration of the conformation and dynamics of phospholamban in model membranes', Physical Chemistry Chemical Physics, vol. 13, no. 45, pp. 20188-20198. https://doi.org/10.1039/c1cp21793c

APA

Manna, M., & Mukhopadhyay, C. (2011). Cholesterol driven alteration of the conformation and dynamics of phospholamban in model membranes. Physical Chemistry Chemical Physics, 13(45), 20188-20198. https://doi.org/10.1039/c1cp21793c

Vancouver

Manna M, Mukhopadhyay C. Cholesterol driven alteration of the conformation and dynamics of phospholamban in model membranes. Physical Chemistry Chemical Physics. 2011 Dec 7;13(45):20188-20198. https://doi.org/10.1039/c1cp21793c

Author

Manna, Moutusi ; Mukhopadhyay, Chaitali. / Cholesterol driven alteration of the conformation and dynamics of phospholamban in model membranes. In: Physical Chemistry Chemical Physics. 2011 ; Vol. 13, No. 45. pp. 20188-20198.

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@article{0d5165aaf32f47aa80c9bdf213567a33,
title = "Cholesterol driven alteration of the conformation and dynamics of phospholamban in model membranes",
abstract = "The effects of cholesterol on various membrane proteins are of long-standing interest in membrane biophysics. Here we present systematic molecular dynamics simulations (totaling 1.4 μs) of integral protein phospholamban incorporated in POPC/cholesterol bilayers (containing 0, 11.11, 22.03, 33.33, and 50 mol{\%} of cholesterol). Phospholamban is a key regulator of cardiac contractility and has recently emerged as a potential drug target. In agreement with experiments, our results show that in a cholesterol-free pure POPC bilayer, phospholamban exhibits broad conformational distribution, ranging from the closed T-state to the extended R-state, crucial for its functionality. Increasing cholesterol concentration progressively stabilizes the bent conformers of phospholamban over open structures, and favors extensive interactions of its amphipathic N-terminal helix with the bilayer surface. The interaction energies between the N-terminal helix of PLB and different POPC/cholesterol bilayers quantitatively confirm its stronger interaction with a higher cholesterol-containing membrane. Simulation with 50 mol{\%} of cholesterol further supports the above conclusions, where phospholamban undergoes rapid conformational transition from extended to closed form, which remains stable for the rest of the simulation time and exhibits the strongest interaction with the membrane. Cholesterol participates in hydrogen-bonding and π-stacking interactions with polar and/or aromatic residues and favors membrane association of phospholamban. We observed cholesterol-enrichment in the neighborhood of phospholamban. Moreover, as a modulator of membrane biophysical properties, cholesterol modifies the hydrophobic matching and trans-membrane tilting of phospholamban and also hinders its 2D-lateral mobility. Altogether, our results highlight atomistic details of protein-lipid interplay and provide new insights into the possible effects of cholesterol on conformational dynamics of phospholamban in membrane bilayers.",
author = "Moutusi Manna and Chaitali Mukhopadhyay",
year = "2011",
month = "12",
day = "7",
doi = "10.1039/c1cp21793c",
language = "English",
volume = "13",
pages = "20188--20198",
journal = "Physical Chemistry Chemical Physics",
issn = "1463-9076",
publisher = "Royal Society of Chemistry",
number = "45",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - Cholesterol driven alteration of the conformation and dynamics of phospholamban in model membranes

AU - Manna, Moutusi

AU - Mukhopadhyay, Chaitali

PY - 2011/12/7

Y1 - 2011/12/7

N2 - The effects of cholesterol on various membrane proteins are of long-standing interest in membrane biophysics. Here we present systematic molecular dynamics simulations (totaling 1.4 μs) of integral protein phospholamban incorporated in POPC/cholesterol bilayers (containing 0, 11.11, 22.03, 33.33, and 50 mol% of cholesterol). Phospholamban is a key regulator of cardiac contractility and has recently emerged as a potential drug target. In agreement with experiments, our results show that in a cholesterol-free pure POPC bilayer, phospholamban exhibits broad conformational distribution, ranging from the closed T-state to the extended R-state, crucial for its functionality. Increasing cholesterol concentration progressively stabilizes the bent conformers of phospholamban over open structures, and favors extensive interactions of its amphipathic N-terminal helix with the bilayer surface. The interaction energies between the N-terminal helix of PLB and different POPC/cholesterol bilayers quantitatively confirm its stronger interaction with a higher cholesterol-containing membrane. Simulation with 50 mol% of cholesterol further supports the above conclusions, where phospholamban undergoes rapid conformational transition from extended to closed form, which remains stable for the rest of the simulation time and exhibits the strongest interaction with the membrane. Cholesterol participates in hydrogen-bonding and π-stacking interactions with polar and/or aromatic residues and favors membrane association of phospholamban. We observed cholesterol-enrichment in the neighborhood of phospholamban. Moreover, as a modulator of membrane biophysical properties, cholesterol modifies the hydrophobic matching and trans-membrane tilting of phospholamban and also hinders its 2D-lateral mobility. Altogether, our results highlight atomistic details of protein-lipid interplay and provide new insights into the possible effects of cholesterol on conformational dynamics of phospholamban in membrane bilayers.

AB - The effects of cholesterol on various membrane proteins are of long-standing interest in membrane biophysics. Here we present systematic molecular dynamics simulations (totaling 1.4 μs) of integral protein phospholamban incorporated in POPC/cholesterol bilayers (containing 0, 11.11, 22.03, 33.33, and 50 mol% of cholesterol). Phospholamban is a key regulator of cardiac contractility and has recently emerged as a potential drug target. In agreement with experiments, our results show that in a cholesterol-free pure POPC bilayer, phospholamban exhibits broad conformational distribution, ranging from the closed T-state to the extended R-state, crucial for its functionality. Increasing cholesterol concentration progressively stabilizes the bent conformers of phospholamban over open structures, and favors extensive interactions of its amphipathic N-terminal helix with the bilayer surface. The interaction energies between the N-terminal helix of PLB and different POPC/cholesterol bilayers quantitatively confirm its stronger interaction with a higher cholesterol-containing membrane. Simulation with 50 mol% of cholesterol further supports the above conclusions, where phospholamban undergoes rapid conformational transition from extended to closed form, which remains stable for the rest of the simulation time and exhibits the strongest interaction with the membrane. Cholesterol participates in hydrogen-bonding and π-stacking interactions with polar and/or aromatic residues and favors membrane association of phospholamban. We observed cholesterol-enrichment in the neighborhood of phospholamban. Moreover, as a modulator of membrane biophysical properties, cholesterol modifies the hydrophobic matching and trans-membrane tilting of phospholamban and also hinders its 2D-lateral mobility. Altogether, our results highlight atomistic details of protein-lipid interplay and provide new insights into the possible effects of cholesterol on conformational dynamics of phospholamban in membrane bilayers.

UR - http://www.scopus.com/inward/record.url?scp=81255129160&partnerID=8YFLogxK

U2 - 10.1039/c1cp21793c

DO - 10.1039/c1cp21793c

M3 - Article

VL - 13

SP - 20188

EP - 20198

JO - Physical Chemistry Chemical Physics

JF - Physical Chemistry Chemical Physics

SN - 1463-9076

IS - 45

ER -