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Molecular Dynamics Simulation Reveals Correlated Inter-Lobe Motion in Protein Lysine Methyltransferase SMYD2.

Spellmon N, Sun X, Sirinupong N, Edwards B, Li C, Yang Z - PLoS ONE (2015)

Bottom Line: Dynamical network analysis defines possible allosteric paths for the correlated dynamics.There are nine communities in the dynamical network with six in the N-lobe and three in the C-lobe, and the communication between the lobes is mediated by a lobe-bridging β hairpin.This study provides insight into the dynamical nature of SMYD2 and could facilitate better understanding of SMYD2 substrate specificity.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, Michigan, United States of America.

ABSTRACT
SMYD proteins are an exciting field of study as they are linked to many types of cancer-related pathways. Cardiac and skeletal muscle development and function also depend on SMYD proteins opening a possible avenue for cardiac-related treatment. Previous crystal structure studies have revealed that this special class of protein lysine methyltransferases have a bilobal structure, and an open-closed motion may regulate substrate specificity. Here we use the molecular dynamics simulation to investigate the still-poorly-understood SMYD2 dynamics. Cross-correlation analysis reveals that SMYD2 exhibits a negative correlated inter-lobe motion. Principle component analysis suggests that this correlated dynamic is contributed to by a twisting motion of the C-lobe with respect to the N-lobe and a clamshell-like motion between the lobes. Dynamical network analysis defines possible allosteric paths for the correlated dynamics. There are nine communities in the dynamical network with six in the N-lobe and three in the C-lobe, and the communication between the lobes is mediated by a lobe-bridging β hairpin. This study provides insight into the dynamical nature of SMYD2 and could facilitate better understanding of SMYD2 substrate specificity.

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Principle component analysis.(A) Scree plot showing the proportion of variance against its eigenvalue rank. (B) Visualization of the motions along PC1 (left) and PC2 (right). The most dissimilar structures along a given PC are depicted by thicker coils. The interpolated structures produced by Bio3D [18] are shown by thinner coils. Color scale from blue, green, to red depicts low to high atomic displacements. (C) Projection of the trajectory onto the planes formed by the first three principle components. Conformers are colored according to the k-means clustering: cluster 1, black; 2, red; 3, blue; 4, green.
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pone.0145758.g002: Principle component analysis.(A) Scree plot showing the proportion of variance against its eigenvalue rank. (B) Visualization of the motions along PC1 (left) and PC2 (right). The most dissimilar structures along a given PC are depicted by thicker coils. The interpolated structures produced by Bio3D [18] are shown by thinner coils. Color scale from blue, green, to red depicts low to high atomic displacements. (C) Projection of the trajectory onto the planes formed by the first three principle components. Conformers are colored according to the k-means clustering: cluster 1, black; 2, red; 3, blue; 4, green.

Mentions: (A) Backbone RMSD during the simulation. RMSD was calculated relative to the crystal structure. (B) Root mean square fluctuation (RMSF) of Cα atoms during the simulation (black line). Red line depicts the RMSF values converted from crystallographic B-factors. The inset depicts the distribution of the simulation RMSF. (C) Ribbon diagram of SMYD2 structure at 2 ns. The structure is colored according to the simulation RMSF. Color scale from blue to red depicts low to high atomic fluctuations. Secondary structures, α-helices and β-strands are labeled and numbered according to their position in the sequence. SAH is represented by sticks and zinc ions by purple spheres. (D) Cross-correlation map of the trajectory. Blue indicates a negative correlation between residue fluctuations, and red depicts a positive correlation. Lobe and domain structures of SMYD2 are indicated on the top of the map. (E) Visualization of residue–residue cross-correlations. SMYD2 is depicted by green coils. Blue and red lines indicate negative and positive correlated motions. (F) Inter-residue distance deviation map. Color scale from blue to magenta depicts small to large distance deviations. (G) Distance fluctuation of Y311–G46 during the simulation. Color bars depict the conformer clustering results obtained in Fig 2.


Molecular Dynamics Simulation Reveals Correlated Inter-Lobe Motion in Protein Lysine Methyltransferase SMYD2.

Spellmon N, Sun X, Sirinupong N, Edwards B, Li C, Yang Z - PLoS ONE (2015)

Principle component analysis.(A) Scree plot showing the proportion of variance against its eigenvalue rank. (B) Visualization of the motions along PC1 (left) and PC2 (right). The most dissimilar structures along a given PC are depicted by thicker coils. The interpolated structures produced by Bio3D [18] are shown by thinner coils. Color scale from blue, green, to red depicts low to high atomic displacements. (C) Projection of the trajectory onto the planes formed by the first three principle components. Conformers are colored according to the k-means clustering: cluster 1, black; 2, red; 3, blue; 4, green.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4696779&req=5

pone.0145758.g002: Principle component analysis.(A) Scree plot showing the proportion of variance against its eigenvalue rank. (B) Visualization of the motions along PC1 (left) and PC2 (right). The most dissimilar structures along a given PC are depicted by thicker coils. The interpolated structures produced by Bio3D [18] are shown by thinner coils. Color scale from blue, green, to red depicts low to high atomic displacements. (C) Projection of the trajectory onto the planes formed by the first three principle components. Conformers are colored according to the k-means clustering: cluster 1, black; 2, red; 3, blue; 4, green.
Mentions: (A) Backbone RMSD during the simulation. RMSD was calculated relative to the crystal structure. (B) Root mean square fluctuation (RMSF) of Cα atoms during the simulation (black line). Red line depicts the RMSF values converted from crystallographic B-factors. The inset depicts the distribution of the simulation RMSF. (C) Ribbon diagram of SMYD2 structure at 2 ns. The structure is colored according to the simulation RMSF. Color scale from blue to red depicts low to high atomic fluctuations. Secondary structures, α-helices and β-strands are labeled and numbered according to their position in the sequence. SAH is represented by sticks and zinc ions by purple spheres. (D) Cross-correlation map of the trajectory. Blue indicates a negative correlation between residue fluctuations, and red depicts a positive correlation. Lobe and domain structures of SMYD2 are indicated on the top of the map. (E) Visualization of residue–residue cross-correlations. SMYD2 is depicted by green coils. Blue and red lines indicate negative and positive correlated motions. (F) Inter-residue distance deviation map. Color scale from blue to magenta depicts small to large distance deviations. (G) Distance fluctuation of Y311–G46 during the simulation. Color bars depict the conformer clustering results obtained in Fig 2.

Bottom Line: Dynamical network analysis defines possible allosteric paths for the correlated dynamics.There are nine communities in the dynamical network with six in the N-lobe and three in the C-lobe, and the communication between the lobes is mediated by a lobe-bridging β hairpin.This study provides insight into the dynamical nature of SMYD2 and could facilitate better understanding of SMYD2 substrate specificity.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, Michigan, United States of America.

ABSTRACT
SMYD proteins are an exciting field of study as they are linked to many types of cancer-related pathways. Cardiac and skeletal muscle development and function also depend on SMYD proteins opening a possible avenue for cardiac-related treatment. Previous crystal structure studies have revealed that this special class of protein lysine methyltransferases have a bilobal structure, and an open-closed motion may regulate substrate specificity. Here we use the molecular dynamics simulation to investigate the still-poorly-understood SMYD2 dynamics. Cross-correlation analysis reveals that SMYD2 exhibits a negative correlated inter-lobe motion. Principle component analysis suggests that this correlated dynamic is contributed to by a twisting motion of the C-lobe with respect to the N-lobe and a clamshell-like motion between the lobes. Dynamical network analysis defines possible allosteric paths for the correlated dynamics. There are nine communities in the dynamical network with six in the N-lobe and three in the C-lobe, and the communication between the lobes is mediated by a lobe-bridging β hairpin. This study provides insight into the dynamical nature of SMYD2 and could facilitate better understanding of SMYD2 substrate specificity.

Show MeSH