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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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SMYD2 dynamics.(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.
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pone.0145758.g001: SMYD2 dynamics.(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.

Mentions: The simulation was performed using NAMD [16]. The starting structure is the crystal structure of SMYD2–SAH complex. The simulation was done in the NVE ensemble. The system was slow heated and equilibrated before 2 ns production simulation. The stability of the system during the production stage was evident by stable kinetic energy, potential energy, temperature, and RMSD (root mean square deviation) (data in S1 Fig and Fig 1A). The protein structure does not significantly deviate from the crystal structure. The backbone RMSD fluctuates between 1.4 Å and 2.5 Å with an average value of 2.0 Å.


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)

SMYD2 dynamics.(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.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0145758.g001: SMYD2 dynamics.(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.
Mentions: The simulation was performed using NAMD [16]. The starting structure is the crystal structure of SMYD2–SAH complex. The simulation was done in the NVE ensemble. The system was slow heated and equilibrated before 2 ns production simulation. The stability of the system during the production stage was evident by stable kinetic energy, potential energy, temperature, and RMSD (root mean square deviation) (data in S1 Fig and Fig 1A). The protein structure does not significantly deviate from the crystal structure. The backbone RMSD fluctuates between 1.4 Å and 2.5 Å with an average value of 2.0 Å.

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
Related in: MedlinePlus