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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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Proposed thermodynamic cycle of peptide insertion and supramolecular assembly inside a model membrane. The yellow arrows depict a pathway in which single peptides insert first into the deep headgroup−core (HG/C) interface and then aggregate to form the final structure. The red arrows mark a less likely (yet plausible) path, in which the peptide aggregates first in solution, and then the aggregate as a whole inserts into the membrane. The green arrows qualitatively describe an intermediary pathway, in which individual peptides insert first into the aqueous or solvent−headgroup (S/HG) interface, aggregate to some extent, and then insert deeper into the membrane. Each of these steps can be described by a free energy change (ΔG, Aggr = aggregation). See the text for further discussion.
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fig7: Proposed thermodynamic cycle of peptide insertion and supramolecular assembly inside a model membrane. The yellow arrows depict a pathway in which single peptides insert first into the deep headgroup−core (HG/C) interface and then aggregate to form the final structure. The red arrows mark a less likely (yet plausible) path, in which the peptide aggregates first in solution, and then the aggregate as a whole inserts into the membrane. The green arrows qualitatively describe an intermediary pathway, in which individual peptides insert first into the aqueous or solvent−headgroup (S/HG) interface, aggregate to some extent, and then insert deeper into the membrane. Each of these steps can be described by a free energy change (ΔG, Aggr = aggregation). See the text for further discussion.

Mentions: The free energy profile presented here is that of a single peptide traveling through the membrane and is thus not reflective of the entire biological process. If the final state of WL5 in the membrane is not monomeric but rather an aggregate form, then it behooves us to study this aggregation process and the pathways that lead to it. Although we have not simulated the actual aggregation, the presented work, coupled with previous simulations and experimental evidence, can shed some light on the mechanism and potential pathways of aggregation. Figure 7 shows a proposed thermodynamic cycle for the insertion and assembly of WL5 in the membrane. In this model, the initial state of the peptide in an aqueous environment is monomeric, and the final state in membrane is an assembly of several monomers (top left and bottom right of Figure 7, respectively). The difference in the free energy between these two states as obtained by Wimley and White is ΔGExp = −5.3 kcal mol−1 (Exp = experimental).(13) [This is assuming that the transfer from monomeric aqueous to membrane aggregate form is an equilibrium process, and that the experimental result is a reflection of this.] As suggested by Grossfield et al., the computed free energy can be coupled to this experimental value via a correction term that accounts for the difference in the peptide and lipid concentrations between simulation and experiment.(30)


Thermodynamics of peptide insertion and aggregation in a lipid bilayer.

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

Proposed thermodynamic cycle of peptide insertion and supramolecular assembly inside a model membrane. The yellow arrows depict a pathway in which single peptides insert first into the deep headgroup−core (HG/C) interface and then aggregate to form the final structure. The red arrows mark a less likely (yet plausible) path, in which the peptide aggregates first in solution, and then the aggregate as a whole inserts into the membrane. The green arrows qualitatively describe an intermediary pathway, in which individual peptides insert first into the aqueous or solvent−headgroup (S/HG) interface, aggregate to some extent, and then insert deeper into the membrane. Each of these steps can be described by a free energy change (ΔG, Aggr = aggregation). See the text for further discussion.
© Copyright Policy - open-access - ccc-price
Related In: Results  -  Collection

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

fig7: Proposed thermodynamic cycle of peptide insertion and supramolecular assembly inside a model membrane. The yellow arrows depict a pathway in which single peptides insert first into the deep headgroup−core (HG/C) interface and then aggregate to form the final structure. The red arrows mark a less likely (yet plausible) path, in which the peptide aggregates first in solution, and then the aggregate as a whole inserts into the membrane. The green arrows qualitatively describe an intermediary pathway, in which individual peptides insert first into the aqueous or solvent−headgroup (S/HG) interface, aggregate to some extent, and then insert deeper into the membrane. Each of these steps can be described by a free energy change (ΔG, Aggr = aggregation). See the text for further discussion.
Mentions: The free energy profile presented here is that of a single peptide traveling through the membrane and is thus not reflective of the entire biological process. If the final state of WL5 in the membrane is not monomeric but rather an aggregate form, then it behooves us to study this aggregation process and the pathways that lead to it. Although we have not simulated the actual aggregation, the presented work, coupled with previous simulations and experimental evidence, can shed some light on the mechanism and potential pathways of aggregation. Figure 7 shows a proposed thermodynamic cycle for the insertion and assembly of WL5 in the membrane. In this model, the initial state of the peptide in an aqueous environment is monomeric, and the final state in membrane is an assembly of several monomers (top left and bottom right of Figure 7, respectively). The difference in the free energy between these two states as obtained by Wimley and White is ΔGExp = −5.3 kcal mol−1 (Exp = experimental).(13) [This is assuming that the transfer from monomeric aqueous to membrane aggregate form is an equilibrium process, and that the experimental result is a reflection of this.] As suggested by Grossfield et al., the computed free energy can be coupled to this experimental value via a correction term that accounts for the difference in the peptide and lipid concentrations between simulation and experiment.(30)

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