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Thermodynamics of peptide insertion and aggregation in a lipid bilayer.

Babakhani A, Gorfe AA, Kim JE, McCammon JA - J Phys Chem B (2008)

Bottom Line: Recent experiments provided valuable data on the free energy changes associated with the transfer of individual amino acids from water to membrane.However, a complete picture of the pathways and the associated changes in energy of peptide insertion into a membrane remains elusive.Combining our results with those in the literature, we present a thermodynamic model for peptide insertion and aggregation which involves peptide aggregation upon contact with the membrane at the solvent-lipid headgroup interface.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry & Biochemistry, and Howard Hughes Medical Institute, University of California at San Diego, 9500 Gilman Drive, MC 0365 La Jolla, California 92093-0365, USA. ababakha@mccammon.ucsd.edu

ABSTRACT
A variety of biomolecules mediate physiological processes by inserting and reorganizing in cell membranes, and the thermodynamic forces responsible for their partitioning are of great interest. Recent experiments provided valuable data on the free energy changes associated with the transfer of individual amino acids from water to membrane. However, a complete picture of the pathways and the associated changes in energy of peptide insertion into a membrane remains elusive. To this end, computational techniques supplement the experimental data with atomic-level details and shed light on the energetics of insertion. Here, we employed the technique of umbrella sampling in a total 850 ns of all-atom molecular dynamics simulations to study the free energy profile and the pathway of insertion of a model hexapeptide consisting of a tryptophan and five leucines (WL5). The computed free energy profile of the peptide as it travels from bulk solvent through the membrane core exhibits two minima: a local minimum at the water-membrane interface or the headgroup region and a global minimum at the hydrophobic-hydrophilic interface close to the lipid glycerol region. A rather small barrier of roughly 1 kcal mol (-1) exists at the membrane core, which is explained by the enhanced flexibility of the peptide when deeply inserted. Combining our results with those in the literature, we present a thermodynamic model for peptide insertion and aggregation which involves peptide aggregation upon contact with the membrane at the solvent-lipid headgroup interface.

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Root mean square fluctuation (RMSF) of the peptide by atom number and as a function of position along the z axis of the simulation box. The membrane is centered on the zero mark of the z axis. Atom numbers 1−3 correspond to the acetyl group on the N-terminus; 4−24 correspond to the tryptophan residue; 25−69 correspond to the leucine residues; and 70−72 correspond to the amide group on the C-terminus. (a) Surface representation, where the red halo shows the maximum RMSF achieved by the indole ring near the core of the membrane. (b) An alternative (color map) view of the RMSF data.
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fig6: Root mean square fluctuation (RMSF) of the peptide by atom number and as a function of position along the z axis of the simulation box. The membrane is centered on the zero mark of the z axis. Atom numbers 1−3 correspond to the acetyl group on the N-terminus; 4−24 correspond to the tryptophan residue; 25−69 correspond to the leucine residues; and 70−72 correspond to the amide group on the C-terminus. (a) Surface representation, where the red halo shows the maximum RMSF achieved by the indole ring near the core of the membrane. (b) An alternative (color map) view of the RMSF data.

Mentions: The peptide descends further into the headgroup−core (HG/C) interface and encounters a global minimum at about ±7 Å and gains a further 2 kcal mol−1 in free energy. The total free energy change from the bulk solvent to the HG/C region (ΔGHG/C) is −10.2 kcal mol−1. A local maximum occurs in the core of the membrane (0 Å), and the energy barrier as measured from the HG/C region is approximately 1.0 kcal mol−1. The peptide exhibits considerable conformational changes as it travels through the membrane. The root-mean-square fluctuation (RMSF) demonstrates how much the peptide deviates from its average conformation and is plotted in Figure 6a as a function of the peptide location along the membrane normal. One can conclude that the peptide is more flexible and samples a wider region of conformational space (has a larger RMSF) as it travels deeper into the membrane core. This flexibility is also demonstrated by the root-mean-square deviation (rmsd) of the peptide structure, as seen in Figure S3 of Supporting Information. An alternative view of the RMSF in Figure 6b further shows that the side chains of the peptide are predominantly responsible for this flexibility. In particular, the TRP side chain has the largest RMSF when deep in the membrane core. To the extent that peptide flexibility can be correlated with entropy,(29) one can infer that the peptide exhibits increased entropy as it inserts into the membrane. This results in a more negative (or favorable) contribution to the free energy change and explains why the energy barrier in the core is not greater in the calculated profile. Therefore, a small barrier seems to suggest that the peptide can occasionally translate across the membrane center and shift positions between the two leaflets. Yet, as Wimley and White have demonstrated and as we shall explore further below, individual units of this model peptide aggregate in the membrane and form a supramolecular structure, a process that can counteract the tendency of a lone peptide to transfer from leaflet to leaflet.14,15


Thermodynamics of peptide insertion and aggregation in a lipid bilayer.

Babakhani A, Gorfe AA, Kim JE, McCammon JA - J Phys Chem B (2008)

Root mean square fluctuation (RMSF) of the peptide by atom number and as a function of position along the z axis of the simulation box. The membrane is centered on the zero mark of the z axis. Atom numbers 1−3 correspond to the acetyl group on the N-terminus; 4−24 correspond to the tryptophan residue; 25−69 correspond to the leucine residues; and 70−72 correspond to the amide group on the C-terminus. (a) Surface representation, where the red halo shows the maximum RMSF achieved by the indole ring near the core of the membrane. (b) An alternative (color map) view of the RMSF data.
© Copyright Policy - open-access - ccc-price
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC2651738&req=5

fig6: Root mean square fluctuation (RMSF) of the peptide by atom number and as a function of position along the z axis of the simulation box. The membrane is centered on the zero mark of the z axis. Atom numbers 1−3 correspond to the acetyl group on the N-terminus; 4−24 correspond to the tryptophan residue; 25−69 correspond to the leucine residues; and 70−72 correspond to the amide group on the C-terminus. (a) Surface representation, where the red halo shows the maximum RMSF achieved by the indole ring near the core of the membrane. (b) An alternative (color map) view of the RMSF data.
Mentions: The peptide descends further into the headgroup−core (HG/C) interface and encounters a global minimum at about ±7 Å and gains a further 2 kcal mol−1 in free energy. The total free energy change from the bulk solvent to the HG/C region (ΔGHG/C) is −10.2 kcal mol−1. A local maximum occurs in the core of the membrane (0 Å), and the energy barrier as measured from the HG/C region is approximately 1.0 kcal mol−1. The peptide exhibits considerable conformational changes as it travels through the membrane. The root-mean-square fluctuation (RMSF) demonstrates how much the peptide deviates from its average conformation and is plotted in Figure 6a as a function of the peptide location along the membrane normal. One can conclude that the peptide is more flexible and samples a wider region of conformational space (has a larger RMSF) as it travels deeper into the membrane core. This flexibility is also demonstrated by the root-mean-square deviation (rmsd) of the peptide structure, as seen in Figure S3 of Supporting Information. An alternative view of the RMSF in Figure 6b further shows that the side chains of the peptide are predominantly responsible for this flexibility. In particular, the TRP side chain has the largest RMSF when deep in the membrane core. To the extent that peptide flexibility can be correlated with entropy,(29) one can infer that the peptide exhibits increased entropy as it inserts into the membrane. This results in a more negative (or favorable) contribution to the free energy change and explains why the energy barrier in the core is not greater in the calculated profile. Therefore, a small barrier seems to suggest that the peptide can occasionally translate across the membrane center and shift positions between the two leaflets. Yet, as Wimley and White have demonstrated and as we shall explore further below, individual units of this model peptide aggregate in the membrane and form a supramolecular structure, a process that can counteract the tendency of a lone peptide to transfer from leaflet to leaflet.14,15

Bottom Line: Recent experiments provided valuable data on the free energy changes associated with the transfer of individual amino acids from water to membrane.However, a complete picture of the pathways and the associated changes in energy of peptide insertion into a membrane remains elusive.Combining our results with those in the literature, we present a thermodynamic model for peptide insertion and aggregation which involves peptide aggregation upon contact with the membrane at the solvent-lipid headgroup interface.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry & Biochemistry, and Howard Hughes Medical Institute, University of California at San Diego, 9500 Gilman Drive, MC 0365 La Jolla, California 92093-0365, USA. ababakha@mccammon.ucsd.edu

ABSTRACT
A variety of biomolecules mediate physiological processes by inserting and reorganizing in cell membranes, and the thermodynamic forces responsible for their partitioning are of great interest. Recent experiments provided valuable data on the free energy changes associated with the transfer of individual amino acids from water to membrane. However, a complete picture of the pathways and the associated changes in energy of peptide insertion into a membrane remains elusive. To this end, computational techniques supplement the experimental data with atomic-level details and shed light on the energetics of insertion. Here, we employed the technique of umbrella sampling in a total 850 ns of all-atom molecular dynamics simulations to study the free energy profile and the pathway of insertion of a model hexapeptide consisting of a tryptophan and five leucines (WL5). The computed free energy profile of the peptide as it travels from bulk solvent through the membrane core exhibits two minima: a local minimum at the water-membrane interface or the headgroup region and a global minimum at the hydrophobic-hydrophilic interface close to the lipid glycerol region. A rather small barrier of roughly 1 kcal mol (-1) exists at the membrane core, which is explained by the enhanced flexibility of the peptide when deeply inserted. Combining our results with those in the literature, we present a thermodynamic model for peptide insertion and aggregation which involves peptide aggregation upon contact with the membrane at the solvent-lipid headgroup interface.

Show MeSH
Related in: MedlinePlus