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Acceleration of Lateral Equilibration in Mixed Lipid Bilayers Using Replica Exchange with Solute Tempering.

Huang K, García AE - J Chem Theory Comput (2014)

Bottom Line: This heterogeneity can result from preferential interactions between membrane components or interactions with membrane proteins.The relative diffusion rate between molecules in REST is, on average, an order of magnitude faster than in the standard MD simulation.Although REST was initially proposed to study protein folding and its efficiency in protein folding is still under debate, we find a unique application of REST to accelerate lateral equilibration in mixed lipid membranes and suggest a promising way to probe membrane lateral heterogeneity through molecular dynamics simulation.

View Article: PubMed Central - PubMed

Affiliation: Department of Physics, Applied Physics and Astronomy, Rensselaer Polytechnic Institute , Troy, New York 12180, United States.

ABSTRACT
The lateral heterogeneity of cellular membranes plays an important role in many biological functions such as signaling and regulating membrane proteins. This heterogeneity can result from preferential interactions between membrane components or interactions with membrane proteins. One major difficulty in molecular dynamics simulations aimed at studying the membrane heterogeneity is that lipids diffuse slowly and collectively in bilayers, and therefore, it is difficult to reach equilibrium in lateral organization in bilayer mixtures. Here, we propose the use of the replica exchange with solute tempering (REST) approach to accelerate lateral relaxation in heterogeneous bilayers. REST is based on the replica exchange method but tempers only the solute, leaving the temperature of the solvent fixed. Since the number of replicas in REST scales approximately only with the degrees of freedom in the solute, REST enables us to enhance the configuration sampling of lipid bilayers with fewer replicas, in comparison with the temperature replica exchange molecular dynamics simulation (T-REMD) where the number of replicas scales with the degrees of freedom of the entire system. We apply the REST method to a cholesterol and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) bilayer mixture and find that the lateral distribution functions of all molecular pair types converge much faster than in the standard MD simulation. The relative diffusion rate between molecules in REST is, on average, an order of magnitude faster than in the standard MD simulation. Although REST was initially proposed to study protein folding and its efficiency in protein folding is still under debate, we find a unique application of REST to accelerate lateral equilibration in mixed lipid membranes and suggest a promising way to probe membrane lateral heterogeneity through molecular dynamics simulation.

No MeSH data available.


Totalfree energy ΔGtotal(r) (solid line) and the excess free energy ΔGex(r) (dashed line) profilesbetween different molecular types as a function of the lateral molecularcenter of mass distance.
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fig7: Totalfree energy ΔGtotal(r) (solid line) and the excess free energy ΔGex(r) (dashed line) profilesbetween different molecular types as a function of the lateral molecularcenter of mass distance.

Mentions: Based onthe high resolution rdf obtained from REST, we calculate the totalGibbs free energy ΔGtotal(r) and excess Gibbs free energy ΔGex(r) profiles between CHOL–CHOL,CHOL–DPPC, and DPPC–DPPC. ΔGtotal(r) and ΔGex(r) are defined as16and17g(r) isthe lateral radial distribution function (rdf), and r0 is the reference distance where we set Gtotal(r0) = 0. Gid(r) is the contribution to the Gtotal(r) due to the Jacobianor area effect in the two-dimensional space. Figure 7 shows that ΔGtotal(r) is always above 0. This means that neither CHOL or DPPCtends to aggregate at the 50% CHOL concentration. Andoh et al. reportedthe CHOL–CHOL Gibbs free energy profile in dilute conditionsand found that ΔGtotal(r) drops below zero in the range 1.0 < r <1.5 nm.33 This difference suggests thatCHOL–CHOL Gtotal(r) depends on CHOL concentration. The DPPC–DPPC Gtotal(r) is almost flat when r > 1.0 nm, suggesting a random distribution of DPPCatlarge distance. Several local minima exist in the CHOL–CHOLΔGtotal(r), indicatingpreferential interacting locations for CHOL–CHOL pairs. Thissupports some phenomenological models, such as the supperlattice model34,35 and umbrella model,36−38 which suggest long-range ordering for CHOL. However,the barriers between the free energy minimums are of the order ofkT scale, suggesting that the ordering of cholesterols is sensitiveto the temperature. As the derivative of ΔGex(r) is the mean force, the ΔGex(r) we obtained can be usedas a reference for various coarse grained models for this system.39,40


Acceleration of Lateral Equilibration in Mixed Lipid Bilayers Using Replica Exchange with Solute Tempering.

Huang K, García AE - J Chem Theory Comput (2014)

Totalfree energy ΔGtotal(r) (solid line) and the excess free energy ΔGex(r) (dashed line) profilesbetween different molecular types as a function of the lateral molecularcenter of mass distance.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4196747&req=5

fig7: Totalfree energy ΔGtotal(r) (solid line) and the excess free energy ΔGex(r) (dashed line) profilesbetween different molecular types as a function of the lateral molecularcenter of mass distance.
Mentions: Based onthe high resolution rdf obtained from REST, we calculate the totalGibbs free energy ΔGtotal(r) and excess Gibbs free energy ΔGex(r) profiles between CHOL–CHOL,CHOL–DPPC, and DPPC–DPPC. ΔGtotal(r) and ΔGex(r) are defined as16and17g(r) isthe lateral radial distribution function (rdf), and r0 is the reference distance where we set Gtotal(r0) = 0. Gid(r) is the contribution to the Gtotal(r) due to the Jacobianor area effect in the two-dimensional space. Figure 7 shows that ΔGtotal(r) is always above 0. This means that neither CHOL or DPPCtends to aggregate at the 50% CHOL concentration. Andoh et al. reportedthe CHOL–CHOL Gibbs free energy profile in dilute conditionsand found that ΔGtotal(r) drops below zero in the range 1.0 < r <1.5 nm.33 This difference suggests thatCHOL–CHOL Gtotal(r) depends on CHOL concentration. The DPPC–DPPC Gtotal(r) is almost flat when r > 1.0 nm, suggesting a random distribution of DPPCatlarge distance. Several local minima exist in the CHOL–CHOLΔGtotal(r), indicatingpreferential interacting locations for CHOL–CHOL pairs. Thissupports some phenomenological models, such as the supperlattice model34,35 and umbrella model,36−38 which suggest long-range ordering for CHOL. However,the barriers between the free energy minimums are of the order ofkT scale, suggesting that the ordering of cholesterols is sensitiveto the temperature. As the derivative of ΔGex(r) is the mean force, the ΔGex(r) we obtained can be usedas a reference for various coarse grained models for this system.39,40

Bottom Line: This heterogeneity can result from preferential interactions between membrane components or interactions with membrane proteins.The relative diffusion rate between molecules in REST is, on average, an order of magnitude faster than in the standard MD simulation.Although REST was initially proposed to study protein folding and its efficiency in protein folding is still under debate, we find a unique application of REST to accelerate lateral equilibration in mixed lipid membranes and suggest a promising way to probe membrane lateral heterogeneity through molecular dynamics simulation.

View Article: PubMed Central - PubMed

Affiliation: Department of Physics, Applied Physics and Astronomy, Rensselaer Polytechnic Institute , Troy, New York 12180, United States.

ABSTRACT
The lateral heterogeneity of cellular membranes plays an important role in many biological functions such as signaling and regulating membrane proteins. This heterogeneity can result from preferential interactions between membrane components or interactions with membrane proteins. One major difficulty in molecular dynamics simulations aimed at studying the membrane heterogeneity is that lipids diffuse slowly and collectively in bilayers, and therefore, it is difficult to reach equilibrium in lateral organization in bilayer mixtures. Here, we propose the use of the replica exchange with solute tempering (REST) approach to accelerate lateral relaxation in heterogeneous bilayers. REST is based on the replica exchange method but tempers only the solute, leaving the temperature of the solvent fixed. Since the number of replicas in REST scales approximately only with the degrees of freedom in the solute, REST enables us to enhance the configuration sampling of lipid bilayers with fewer replicas, in comparison with the temperature replica exchange molecular dynamics simulation (T-REMD) where the number of replicas scales with the degrees of freedom of the entire system. We apply the REST method to a cholesterol and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) bilayer mixture and find that the lateral distribution functions of all molecular pair types converge much faster than in the standard MD simulation. The relative diffusion rate between molecules in REST is, on average, an order of magnitude faster than in the standard MD simulation. Although REST was initially proposed to study protein folding and its efficiency in protein folding is still under debate, we find a unique application of REST to accelerate lateral equilibration in mixed lipid membranes and suggest a promising way to probe membrane lateral heterogeneity through molecular dynamics simulation.

No MeSH data available.