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Concerted dynamic motions of an FABP4 model and its ligands revealed by microsecond molecular dynamics simulations.

Li Y, Li X, Dong Z - Biochemistry (2014)

Bottom Line: The dynamics of one ligand-free FABP4 and four ligand-bound FABP4s is compared via multiple 1.2 μs simulations.Coupled with opening and closing of FABP4, the ligand adopts distinct binding modes, which are identified and compared with crystal structures.Thus, this work provides details about how ligand binding affects the conformational preference of FABP4 and how ligand binding is coupled with a conformational change of FABP4 at an atomic level.

View Article: PubMed Central - PubMed

Affiliation: The Hormel Institute, University of Minnesota , Austin, Minnesota 55912, United States.

ABSTRACT
In this work, we investigate the dynamic motions of fatty acid binding protein 4 (FABP4) in the absence and presence of a ligand by explicitly solvated all-atom molecular dynamics simulations. The dynamics of one ligand-free FABP4 and four ligand-bound FABP4s is compared via multiple 1.2 μs simulations. In our simulations, the protein interconverts between the open and closed states. Ligand-free FABP4 prefers the closed state, whereas ligand binding induces a conformational transition to the open state. Coupled with opening and closing of FABP4, the ligand adopts distinct binding modes, which are identified and compared with crystal structures. The concerted dynamics of protein and ligand suggests that there may exist multiple FABP4-ligand binding conformations. Thus, this work provides details about how ligand binding affects the conformational preference of FABP4 and how ligand binding is coupled with a conformational change of FABP4 at an atomic level.

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Population of the closed state in the absence and presence of aligand. Population of the closed state is obtained by integrationof the population distribution along the Thr29–Phe57 distancecoordinate between 0 and 8.5 Å.
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fig5: Population of the closed state in the absence and presence of aligand. Population of the closed state is obtained by integrationof the population distribution along the Thr29–Phe57 distancecoordinate between 0 and 8.5 Å.

Mentions: Time-dependence plots of theThr29–Phe57 distance (Figure 4A) showthat the protein interconverts repeatedly between the open and closedforms in all MD simulations, suggesting that FABP4 is in a dynamicequilibrium and undergoes rapid fluctuation with or without a ligand.On calculated 1D free energy surfaces (Figure 4B), a handful of energy wells are observable. For apo-FABP4, thedeepest basin appears at 7.7 Å, suggesting that the closed formis preferred. A shallow basin positioned at 10.3 Å correspondsto the open form. For FABP4–ACD, one deep basin is observableat 10.3 Å with an energy barrier of 1.0 kcal mol–1 between the open and closed forms, indicating that the open formis the most populated ensemble (Figure 5).For the other three complexes (FABP4–ANS, FABP4–TGZ,and FABP4–AOB), two deep basins, corresponding to the openand closed forms, are observable, indicating that both of them arethermodynamically stable. The curves in Figure 4B are plotted with a bin width of 0.1 Å. FES curves with variousbin sizes are shown in Figure S2. We findthat the bin width has little effect on the 1D FES when it is between0.1 and 0.5 Å. The energy difference between the basins is lessthan 1.0 kcal mol–1, suggesting that the transitionbetween the open and closed forms may occur easily with little energycost.


Concerted dynamic motions of an FABP4 model and its ligands revealed by microsecond molecular dynamics simulations.

Li Y, Li X, Dong Z - Biochemistry (2014)

Population of the closed state in the absence and presence of aligand. Population of the closed state is obtained by integrationof the population distribution along the Thr29–Phe57 distancecoordinate between 0 and 8.5 Å.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4196735&req=5

fig5: Population of the closed state in the absence and presence of aligand. Population of the closed state is obtained by integrationof the population distribution along the Thr29–Phe57 distancecoordinate between 0 and 8.5 Å.
Mentions: Time-dependence plots of theThr29–Phe57 distance (Figure 4A) showthat the protein interconverts repeatedly between the open and closedforms in all MD simulations, suggesting that FABP4 is in a dynamicequilibrium and undergoes rapid fluctuation with or without a ligand.On calculated 1D free energy surfaces (Figure 4B), a handful of energy wells are observable. For apo-FABP4, thedeepest basin appears at 7.7 Å, suggesting that the closed formis preferred. A shallow basin positioned at 10.3 Å correspondsto the open form. For FABP4–ACD, one deep basin is observableat 10.3 Å with an energy barrier of 1.0 kcal mol–1 between the open and closed forms, indicating that the open formis the most populated ensemble (Figure 5).For the other three complexes (FABP4–ANS, FABP4–TGZ,and FABP4–AOB), two deep basins, corresponding to the openand closed forms, are observable, indicating that both of them arethermodynamically stable. The curves in Figure 4B are plotted with a bin width of 0.1 Å. FES curves with variousbin sizes are shown in Figure S2. We findthat the bin width has little effect on the 1D FES when it is between0.1 and 0.5 Å. The energy difference between the basins is lessthan 1.0 kcal mol–1, suggesting that the transitionbetween the open and closed forms may occur easily with little energycost.

Bottom Line: The dynamics of one ligand-free FABP4 and four ligand-bound FABP4s is compared via multiple 1.2 μs simulations.Coupled with opening and closing of FABP4, the ligand adopts distinct binding modes, which are identified and compared with crystal structures.Thus, this work provides details about how ligand binding affects the conformational preference of FABP4 and how ligand binding is coupled with a conformational change of FABP4 at an atomic level.

View Article: PubMed Central - PubMed

Affiliation: The Hormel Institute, University of Minnesota , Austin, Minnesota 55912, United States.

ABSTRACT
In this work, we investigate the dynamic motions of fatty acid binding protein 4 (FABP4) in the absence and presence of a ligand by explicitly solvated all-atom molecular dynamics simulations. The dynamics of one ligand-free FABP4 and four ligand-bound FABP4s is compared via multiple 1.2 μs simulations. In our simulations, the protein interconverts between the open and closed states. Ligand-free FABP4 prefers the closed state, whereas ligand binding induces a conformational transition to the open state. Coupled with opening and closing of FABP4, the ligand adopts distinct binding modes, which are identified and compared with crystal structures. The concerted dynamics of protein and ligand suggests that there may exist multiple FABP4-ligand binding conformations. Thus, this work provides details about how ligand binding affects the conformational preference of FABP4 and how ligand binding is coupled with a conformational change of FABP4 at an atomic level.

Show MeSH
Related in: MedlinePlus