Orientation and Conformational Preference of Leucine-Enkephalin at the Surface of a Hydrated Dimyristoylphosphatidylcholine Bilayer:  NMR and MD Simulation

Chandrasekhar, Indira; Gunsteren, Wilfred F. van; Zandomeneghi, Giorgia; Williamson, Philip T. F.; Meier, Beat H.

doi:10.1021/ja054785q

Cited by 21 publications

(58 citation statements)

References 51 publications

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“…However, the oscillations render it difficult to obtain reliable time constants, especially for the one in the intermediate range. In agreement with the previous study, 14 our simulations in water and bilayer show that the strongest secondary structure feature is a bend at residue 3, whereas residues 2 and 4 occasionally adopt turn conformations. For example, the bend at residue 3 dominates for 92 and 97% of the time in Lenk 3 and Lenk 4, respectively.…”

Section: Waiting-time-dependent 2d Ir Spectra and Frequencyfrequency supporting

confidence: 93%

Interactions of Tyrosine in Leu-Enkephalin at a Membrane−Water Interface: An Ultrafast Two-Dimensional Infrared Study Combined with Density Functional Calculations and Molecular Dynamics Simulations

Sul

Feng

et al. 2009

J. Phys. Chem. B

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The interactions of neuropeptides and membranes play an important role in peptide hormone function. Our current understanding of peptide-membrane interactions remains limited due to the paucity of experimental techniques capable of probing such interactions. In this work, we study the nature of opioid peptide-membrane interactions using ultrafast two-dimensional infrared (2D IR) spectroscopy. The high temporal resolution of 2D IR is particularly suited for studying highly flexible opioid peptides. We investigate the location of the tyrosine (Tyr) side chain of leucine-enkephalin (Lenk) in lipid bilayer membranes by measuring spectral diffusion of the phenolic ring vibrational mode in three different systems: Lenk in lipid bilayer membranes (bicelles), Lenk in deuterated water, and p-cresol in deuterated water. Frequency-frequency correlation functions obtained from waiting-time-dependent 2D IR spectra reveal an ultrafast decaying component with an approximately 1 ps time constant that is common for all three systems. On the basis of density functional theory calculations and molecular dynamics simulations, this spectral diffusion component is attributed to hydrogen-bond dynamics of the phenolic hydroxyl group interacting with bulk water. Unlike p-cresol in water, both Lenk systems exhibit static spectral inhomogeneity, which can be attributed to conformational distributions of Lenk that do not interconvert within 4 ps. Our results suggest that the Tyr side chain of Lenk in bicelles is located at the water-abundant region at the membrane-water interface and not embedded into the hydrophobic core.

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Section: Waiting-time-dependent 2d Ir Spectra and Frequencyfrequency supporting

confidence: 93%

Interactions of Tyrosine in Leu-Enkephalin at a Membrane−Water Interface: An Ultrafast Two-Dimensional Infrared Study Combined with Density Functional Calculations and Molecular Dynamics Simulations

Sul

Feng

et al. 2009

J. Phys. Chem. B

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“…For example, MD simulations have yielded a unique structure of gramicidin when combined with solid-state NMR structural constraints obtained from mechanically aligned bilayers (66). In addition, a recent study combining MD simulations with NMR determined the orientation and conformational preference of leucine-enkephalin in DMPC bilayers (67). Similar studies are increasingly being carried out in several laboratories.…”

Section: Discussionmentioning

confidence: 99%

Structure, Topology, and Tilt of Cell-Signaling Peptides Containing Nuclear Localization Sequences in Membrane Bilayers Determined by Solid-State NMR and Molecular Dynamics Simulation Studies

et al. 2007

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Cell-signaling peptides have been extensively used to transport functional molecules across the plasma membrane into living cells. These peptides consist of a hydrophobic sequence and a cationic nuclear localization sequence (NLS). It has been assumed that the hydrophobic region penetrates through the hydrophobic lipid bilayer and delivers the NLS inside the cell. To better understand the transport mechanism of these peptides, in this study, we investigated the structure, orientation, tilt of the peptide relative to the bilayer normal, and the membraneinteraction of two cell-signaling peptides, SA and SKP. Results from CD and solid-state NMR experiments combined with molecular dynamics simulations suggest that the hydrophobic region is helical and has a transmembrane orientation with the helical axis tilted away from the bilayer normal. The influence of the hydrophobic mismatch, between the hydrophobic length of the peptide and the hydrophobic thickness of the bilayer, on the tilt angle of the peptides was investigated using thicker POPC and thinner DMPC bilayers. NMR experiments showed that the hydrophobic domain of each peptide has a tilt angle of 15±3° in POPC, while in DMPC 25±3° and 30±3° tilts were observed for SA and SKP peptides respectively. These results are in good agreement with molecular dynamics simulations, which predicts a tilt angle of 13.3° (SA in POPC), 16.4° (SKP in POPC), 22.3° (SA in DMPC) and 31.7°( SKP in POPC). These results and simulations on the hydrophobic fragment of SA or SKP suggest that the tilt of helices increases with a decrease in the bilayer thickness without changing the phase, order, and structure of the lipid bilayers. KeywordsCell-permeable peptides; NLS; PISA wheel; tilt; hydrophobic mismatch; transmembrane helix Noninvasive delivery of peptides, proteins, oligonucleotides and other functional cargo molecules into living cells is highly dependent on their efficient transport across the plasma membrane barrier (1-7). Hydrophobic peptides have been successfully used to transport nuclear localization sequences (NLS) in order to probe intracellular signaling, which involved

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“…Besides yielding the topology of membrane-bound α-helices, dipolar waves can also be used as input for the structure calculation of micelle-bound proteins as shown for the helical membrane protein phospholamban [33]. Inherent flexibility of smaller peptides in a membrane-mimetic leads to reduced RDCs as was found for the pentapeptide Leu-enkephalin bound to the surface of DMPC bilayers [34]. Polyacrylamide gels are typical alignment media which can be used for peptides bound to membrane-mimetics, while filamentous phages cannot be employed due to their incompatibility with detergents [35].…”

Section: Solution Nmrmentioning

confidence: 99%

Determining the Orientation and Localization of Membrane-Bound Peptides

Hohlweg

Kosol²,

Zangger³

2012

CPPS

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Many naturally occurring bioactive peptides bind to biological membranes. Studying and elucidating the mode of interaction is often an essential step to understand their molecular and biological functions. To obtain the complete orientation and immersion depth of such compounds in the membrane or a membrane-mimetic system, a number of methods are available, which are separated in this review into four main classes: solution NMR, solid-state NMR, EPR and other methods. Solution NMR methods include the Nuclear Overhauser Effect (NOE) between peptide and membrane signals, residual dipolar couplings and the use of paramagnetic probes, either within the membrane-mimetic or in the solvent. The vast array of solid state NMR methods to study membrane-bound peptide orientation and localization includes the anisotropic chemical shift, PISA wheels, dipolar waves, the GALA, MAOS and REDOR methods and again the use of paramagnetic additives on relaxation rates. Paramagnetic additives, with their effect on spectral linewidths, have also been used in EPR spectroscopy. Additionally, the orientation of a peptide within a membrane can be obtained by the anisotropic hyperfine tensor of a rigidly attached nitroxide label. Besides these magnetic resonance techniques a series of other methods to probe the orientation of peptides in membranes has been developed, consisting of fluorescence-, infrared- and oriented circular dichroism spectroscopy, colorimetry, interface-sensitive X-ray and neutron scattering and Quartz crystal microbalance.

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Orientation and Conformational Preference of Leucine-Enkephalin at the Surface of a Hydrated Dimyristoylphosphatidylcholine Bilayer: NMR and MD Simulation

Cited by 21 publications

References 51 publications

Interactions of Tyrosine in Leu-Enkephalin at a Membrane−Water Interface: An Ultrafast Two-Dimensional Infrared Study Combined with Density Functional Calculations and Molecular Dynamics Simulations

Interactions of Tyrosine in Leu-Enkephalin at a Membrane−Water Interface: An Ultrafast Two-Dimensional Infrared Study Combined with Density Functional Calculations and Molecular Dynamics Simulations

Structure, Topology, and Tilt of Cell-Signaling Peptides Containing Nuclear Localization Sequences in Membrane Bilayers Determined by Solid-State NMR and Molecular Dynamics Simulation Studies

Determining the Orientation and Localization of Membrane-Bound Peptides

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