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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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Representative structures of populated ensembleson 2D free energysurfaces. (A) Superposition of ligands in the crystal structure andstate X in Figure 6. Carbons in the crystalstructure are white, and carbons in X are green. (B) Representativestructure of S3 for the FABP4–ACD complex. In S3, FABP4 adoptsthe closed form and ACD stretches out of the binding cavity from theaperture enclosed by Val80 and Trp97. (C) Representative structuresof S1 and S2 for FABP4–ANS. (D) Representative structures ofS1 and S2 for FABP4–TGZ. (E) Representative structures of S1and S2 for FABP4–AOB. Carbons of ligands are green, carbonsof residues are cyan, oxygen is red, nitrogen is blue, and sulfuris yellow.
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fig7: Representative structures of populated ensembleson 2D free energysurfaces. (A) Superposition of ligands in the crystal structure andstate X in Figure 6. Carbons in the crystalstructure are white, and carbons in X are green. (B) Representativestructure of S3 for the FABP4–ACD complex. In S3, FABP4 adoptsthe closed form and ACD stretches out of the binding cavity from theaperture enclosed by Val80 and Trp97. (C) Representative structuresof S1 and S2 for FABP4–ANS. (D) Representative structures ofS1 and S2 for FABP4–TGZ. (E) Representative structures of S1and S2 for FABP4–AOB. Carbons of ligands are green, carbonsof residues are cyan, oxygen is red, nitrogen is blue, and sulfuris yellow.

Mentions: With the order parameters, two-dimensionalFESs of FABP4–ligand complexes were calculated. On the surfaces,we found a handful of well-defined basins, suggesting multiple bindingmodes between the protein and ligands (Figure 6). Snapshot structures in each energy well were collected and compared.One representative structure for each basin was selected with thescript of average_structure implemented in Maestro v9.3. The representativestructures were then compared with crystal structures. In Figure 6, the populated ensemble X corresponds to the crystalstructure. The heavy-atom RMSD of ligand in X with respect to thecrystal structure is 2.0, 1.3, 0.7, and 1.0 Å, respectively,for FABP4–ACD, FABP4–ANS, FABP4–TGZ, and FABP4–AOBafter alignment of protein structures (Figure 7A), indicating the successful reproduction of the binding mode thatwas experimentally determined.


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

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

Representative structures of populated ensembleson 2D free energysurfaces. (A) Superposition of ligands in the crystal structure andstate X in Figure 6. Carbons in the crystalstructure are white, and carbons in X are green. (B) Representativestructure of S3 for the FABP4–ACD complex. In S3, FABP4 adoptsthe closed form and ACD stretches out of the binding cavity from theaperture enclosed by Val80 and Trp97. (C) Representative structuresof S1 and S2 for FABP4–ANS. (D) Representative structures ofS1 and S2 for FABP4–TGZ. (E) Representative structures of S1and S2 for FABP4–AOB. Carbons of ligands are green, carbonsof residues are cyan, oxygen is red, nitrogen is blue, and sulfuris yellow.
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fig7: Representative structures of populated ensembleson 2D free energysurfaces. (A) Superposition of ligands in the crystal structure andstate X in Figure 6. Carbons in the crystalstructure are white, and carbons in X are green. (B) Representativestructure of S3 for the FABP4–ACD complex. In S3, FABP4 adoptsthe closed form and ACD stretches out of the binding cavity from theaperture enclosed by Val80 and Trp97. (C) Representative structuresof S1 and S2 for FABP4–ANS. (D) Representative structures ofS1 and S2 for FABP4–TGZ. (E) Representative structures of S1and S2 for FABP4–AOB. Carbons of ligands are green, carbonsof residues are cyan, oxygen is red, nitrogen is blue, and sulfuris yellow.
Mentions: With the order parameters, two-dimensionalFESs of FABP4–ligand complexes were calculated. On the surfaces,we found a handful of well-defined basins, suggesting multiple bindingmodes between the protein and ligands (Figure 6). Snapshot structures in each energy well were collected and compared.One representative structure for each basin was selected with thescript of average_structure implemented in Maestro v9.3. The representativestructures were then compared with crystal structures. In Figure 6, the populated ensemble X corresponds to the crystalstructure. The heavy-atom RMSD of ligand in X with respect to thecrystal structure is 2.0, 1.3, 0.7, and 1.0 Å, respectively,for FABP4–ACD, FABP4–ANS, FABP4–TGZ, and FABP4–AOBafter alignment of protein structures (Figure 7A), indicating the successful reproduction of the binding mode thatwas experimentally determined.

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