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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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Free energy profile (symmetric-heavy blue line, asymmetric-dashed line) of the peptide as a function of position along the z dimension (negative/positive values correspond to the lower/upper leaflets, respectively). Aqua green on either side of the simulation box denotes regions of bulk solvent. Pink marks the regions of the solvent/lipid headgroup interface (S/HG in the lower leaflet, HG/S in the upper). Beige indicates the headgroup/core interface (HG/C in the lower leaflet, C/HG in the upper). The light brown region centered on the zero depicts the membrane core. See the text for further discussion and the computed changes in free energy.
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fig1: Free energy profile (symmetric-heavy blue line, asymmetric-dashed line) of the peptide as a function of position along the z dimension (negative/positive values correspond to the lower/upper leaflets, respectively). Aqua green on either side of the simulation box denotes regions of bulk solvent. Pink marks the regions of the solvent/lipid headgroup interface (S/HG in the lower leaflet, HG/S in the upper). Beige indicates the headgroup/core interface (HG/C in the lower leaflet, C/HG in the upper). The light brown region centered on the zero depicts the membrane core. See the text for further discussion and the computed changes in free energy.

Mentions: Each leaflet of the membrane can be divided into three regions based on the polarity of the constituent atoms: the solvent−headgroup interface (S/HG), where the first two solvent shells (∼ 6 Å) merge with the choline and phosphate head groups of the phospholipids; the glycerol or headgroup−core interface (HG/C), where the lipid head groups mix with the hydrophobic fatty acid chains; and the core, the region occupied by the aliphatic lipid tails. By using these three regions as landmarks, the free energy profile of the peptide WL5 as it traverses across the membrane is shown in Figure 1. See Supporting Information for a figure (S1) demonstrating the extent of convergence of this profile (in the allotted sampling time). The profile exhibits minima at both the S/HG and the HG/C interfaces of each leaflet, the latter being the global minimum. Note that two peptide orientations (one per leaflet) were used to determine whether the initial orientation affects the energetics of insertion. The dashed line in Figure 1 clearly shows that the initial orientation does indeed affect the profile. Such an asymmetric profile implies that even for a rudimentary peptide such as WL5, there may be more than one possible path of membrane insertion.


Thermodynamics of peptide insertion and aggregation in a lipid bilayer.

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

Free energy profile (symmetric-heavy blue line, asymmetric-dashed line) of the peptide as a function of position along the z dimension (negative/positive values correspond to the lower/upper leaflets, respectively). Aqua green on either side of the simulation box denotes regions of bulk solvent. Pink marks the regions of the solvent/lipid headgroup interface (S/HG in the lower leaflet, HG/S in the upper). Beige indicates the headgroup/core interface (HG/C in the lower leaflet, C/HG in the upper). The light brown region centered on the zero depicts the membrane core. See the text for further discussion and the computed changes in free energy.
© Copyright Policy - open-access - ccc-price
Related In: Results  -  Collection

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

fig1: Free energy profile (symmetric-heavy blue line, asymmetric-dashed line) of the peptide as a function of position along the z dimension (negative/positive values correspond to the lower/upper leaflets, respectively). Aqua green on either side of the simulation box denotes regions of bulk solvent. Pink marks the regions of the solvent/lipid headgroup interface (S/HG in the lower leaflet, HG/S in the upper). Beige indicates the headgroup/core interface (HG/C in the lower leaflet, C/HG in the upper). The light brown region centered on the zero depicts the membrane core. See the text for further discussion and the computed changes in free energy.
Mentions: Each leaflet of the membrane can be divided into three regions based on the polarity of the constituent atoms: the solvent−headgroup interface (S/HG), where the first two solvent shells (∼ 6 Å) merge with the choline and phosphate head groups of the phospholipids; the glycerol or headgroup−core interface (HG/C), where the lipid head groups mix with the hydrophobic fatty acid chains; and the core, the region occupied by the aliphatic lipid tails. By using these three regions as landmarks, the free energy profile of the peptide WL5 as it traverses across the membrane is shown in Figure 1. See Supporting Information for a figure (S1) demonstrating the extent of convergence of this profile (in the allotted sampling time). The profile exhibits minima at both the S/HG and the HG/C interfaces of each leaflet, the latter being the global minimum. Note that two peptide orientations (one per leaflet) were used to determine whether the initial orientation affects the energetics of insertion. The dashed line in Figure 1 clearly shows that the initial orientation does indeed affect the profile. Such an asymmetric profile implies that even for a rudimentary peptide such as WL5, there may be more than one possible path of membrane insertion.

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