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Testing of the implicit membrane model

(read about implicit membrane model)

Hydrophobic segment (69–97) of human glycophorin A (GpA)

One of the most suitable objects for model testing is the hydrophobic segment of human glycophorin A (GpA). This peptide is relatively short (29 residues), which significantly simplifies treatment of the simulation results. Structure of this peptide had been determined via NMR spectroscopy in DPC micelles. And, finally, it forms dimers in the membrane environment, thus hereafter its investigation could be expanded on analysis of protein–protein interaction in membrane.

Evolution of the peptide structure during the MC procedure.

On the first step of simulations, calculation protocol, tested in the analysis of poly-Leu, was used. Low-energy structures had formed two structural groups: (1) transmembrane α-helix and (2) helical hairpin (see figure). Its conformational energies were closed, so proposed model could not range these states. Possible cause of such structural heterogeneity consists in symmetrical properties of implicit membrane. Natural cell membranes are strongly asymmetric by lipid composition, transmembrane electrostatic potential etc. To take into account this asymmetry membrane model has been elaborated by addition of term mimic influence of transmembrane electrostatic potential.

MC conformational search was prolonged with modified membrane model. As a result only native-like TM conformations were observed in low-energy structural set.

Fusogenic peptide of Influenza A hemagglutinin (HA) and its homologs

Correlation of simulations results and experimental data validates applicability of the membrane model to the analysis of interaction of helical peptides with the membrane. Thus, we can use this approach in study of the peptides with lack of experimental information. One of such type of objects is fusogenic peptides. The purpose of this investigation was delineation of features connected with fusogenic activity of the peptides.

HA and set of its analogs with and without fusogenic activity were analyzed on their mode of membrane binding and distribution of hydrophobic properties along the peptide.

Two-dimensional isopotential maps of the molecular hydrophobicity potential (MHP) on the surfaces of peptides D4 (a) and E5NN (b). Both peptides have α-helical structures which correspond to the lowest-energy conformers found in the result of Monte Carlo simulation. The value on the X axis corresponds to the rotation angle about the helix axis; parameter on Y-axis is the distance along helix axis. Only the hydrophobic areas with MHP>0.100 a.u. are shown. Contour intervals are 0.015 MHP units. The positions of residues are indicated by letters and numbers. Thick straight lines Z=aα+b minimize the sum |Zi−aαi−b| for the set of points (αi, Zi) with MHP>0.12.

Results:

1. Common properties for active and inactive peptides:
   • interfacial binding, preferential exposure of nonpolar and polar groups of peptides in hydrophobic milieu of membrane and in water, respectively.
   • High degree of α-helicity.
   • Membrane insertion with the N-terminus.
2. Specific features inherent in fusion active peptides:
   • Well-defined depth of penetration into membrane.
   • Presence of “oblique-oriented” hydrophobicity pattern on the peptide surface.
3. An algorithm for recognition in protein sequences the segments with potential fusion and strong membrane-destabilizing activities is proposed.

Read about molecular hydrophobicity potential (MHP).

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