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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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Nitrogen heteroatom distribution along the reaction coordinate. (a) Density distributions of the tryptophan indole nitrogen in the upper and lower leaflets of four simulation windows. Dashed lines indicate where the peptide was constrained (via the indole ring) in that particular simulation. (b) The asymmetric free energy profile in the membrane (dashed line) and the same profile shifted to reflect the nitrogen heteroatom position (dark heavy line). At each point, the nitrogen is distributed to the right (more positive z) of the indole center; but the magnitude of that shift is not equal in all parts of the profile.
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fig2: Nitrogen heteroatom distribution along the reaction coordinate. (a) Density distributions of the tryptophan indole nitrogen in the upper and lower leaflets of four simulation windows. Dashed lines indicate where the peptide was constrained (via the indole ring) in that particular simulation. (b) The asymmetric free energy profile in the membrane (dashed line) and the same profile shifted to reflect the nitrogen heteroatom position (dark heavy line). At each point, the nitrogen is distributed to the right (more positive z) of the indole center; but the magnitude of that shift is not equal in all parts of the profile.

Mentions: In the upper leaflet, the nitrogen heteroatom points toward the interfacial regions while the peptide moves through the membrane; while in the lower leaflet, the ring nitrogen consistently points toward the core of the membrane (see Figure 2 and Figure 3). This preferential orientation results in distinct and deeper energy minima at the interfacial regions of the upper leaflet while the corresponding minima in the lower leaflet are shallow and less distinct (see Figure 1 and Figure 2b). The location of the minima and the orientation of the indole ring in the upper leaflet indicate that the ring is in a prime position to interact with the glycerol carbonyls and other hydrogen bonding elements of the lipid head groups. The importance and extent of hydrogen bonding between the indole ring and the membrane interfacial region has been addressed in a previous study.(26) Here, the nitrogen heteroatom forms a significant number of hydrogen bonds with the membrane, and it does so to a greater extent where the minima occur along the reaction coordinate (see Figure 4). In the upper leaflet, where the minima are deeper and more distinct, a larger number of hydrogen bonds are formed as compared with the minima in the lower leaflet.


Thermodynamics of peptide insertion and aggregation in a lipid bilayer.

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

Nitrogen heteroatom distribution along the reaction coordinate. (a) Density distributions of the tryptophan indole nitrogen in the upper and lower leaflets of four simulation windows. Dashed lines indicate where the peptide was constrained (via the indole ring) in that particular simulation. (b) The asymmetric free energy profile in the membrane (dashed line) and the same profile shifted to reflect the nitrogen heteroatom position (dark heavy line). At each point, the nitrogen is distributed to the right (more positive z) of the indole center; but the magnitude of that shift is not equal in all parts of the profile.
© Copyright Policy - open-access - ccc-price
Related In: Results  -  Collection

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

fig2: Nitrogen heteroatom distribution along the reaction coordinate. (a) Density distributions of the tryptophan indole nitrogen in the upper and lower leaflets of four simulation windows. Dashed lines indicate where the peptide was constrained (via the indole ring) in that particular simulation. (b) The asymmetric free energy profile in the membrane (dashed line) and the same profile shifted to reflect the nitrogen heteroatom position (dark heavy line). At each point, the nitrogen is distributed to the right (more positive z) of the indole center; but the magnitude of that shift is not equal in all parts of the profile.
Mentions: In the upper leaflet, the nitrogen heteroatom points toward the interfacial regions while the peptide moves through the membrane; while in the lower leaflet, the ring nitrogen consistently points toward the core of the membrane (see Figure 2 and Figure 3). This preferential orientation results in distinct and deeper energy minima at the interfacial regions of the upper leaflet while the corresponding minima in the lower leaflet are shallow and less distinct (see Figure 1 and Figure 2b). The location of the minima and the orientation of the indole ring in the upper leaflet indicate that the ring is in a prime position to interact with the glycerol carbonyls and other hydrogen bonding elements of the lipid head groups. The importance and extent of hydrogen bonding between the indole ring and the membrane interfacial region has been addressed in a previous study.(26) Here, the nitrogen heteroatom forms a significant number of hydrogen bonds with the membrane, and it does so to a greater extent where the minima occur along the reaction coordinate (see Figure 4). In the upper leaflet, where the minima are deeper and more distinct, a larger number of hydrogen bonds are formed as compared with the minima in the lower leaflet.

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