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The molecular dynamics of Trypanosoma brucei UDP-galactose 4'-epimerase: a drug target for African sleeping sickness.

Friedman AJ, Durrant JD, Pierce LC, McCorvie TJ, Timson DJ, McCammon JA - Chem Biol Drug Des (2012)

Bottom Line: As current drug treatments are either highly toxic or ineffective, novel trypanocides are urgently needed.The sampled conformations and protein dynamics depend not only on the presence of a UDP-sugar ligand, but also on the chirality of the UDP-sugar C4 atom.This dependence provides important insights into TbGalE function and may help guide future computer-aided drug discovery efforts targeting this protein.

View Article: PubMed Central - PubMed

Affiliation: Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, CA 92093-0365, USA. a1friedm@ucsd.edu

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Related in: MedlinePlus

Trajectory RMSD. Each dimer simulation was aligned to the first frame by minimizing the root-mean-square deviation (RMSD) of the Cα’s. RMSD was calculated using the first frame as a reference. For this plot, and in subsequent figures, apo is depicted in black, UDP-galactose in blue, UDP-glucose in red, and the UDP-ketose intermediate in brown. As each substrate was derived from UDP-galactose, the systems needed 9 nseconds to equilibrate (gray box). Trajectory analysis was performed on the subsequent 50 nseconds of each dimer simulation.
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fig02: Trajectory RMSD. Each dimer simulation was aligned to the first frame by minimizing the root-mean-square deviation (RMSD) of the Cα’s. RMSD was calculated using the first frame as a reference. For this plot, and in subsequent figures, apo is depicted in black, UDP-galactose in blue, UDP-glucose in red, and the UDP-ketose intermediate in brown. As each substrate was derived from UDP-galactose, the systems needed 9 nseconds to equilibrate (gray box). Trajectory analysis was performed on the subsequent 50 nseconds of each dimer simulation.

Mentions: Alpha carbon RMSD plots of each homodimer trajectory are shown in Figure 2. As the initial protein conformation of each system was that of the crystallographic UDP-galactose-bound state, the first 9 nseconds of each homodimer simulation were discarded to account for system equilibration. The remaining 50 nseconds of the dimeric simulation were used for subsequent analysis. In total, 400 nseconds of productive TbGalE monomer simulation were generated.


The molecular dynamics of Trypanosoma brucei UDP-galactose 4'-epimerase: a drug target for African sleeping sickness.

Friedman AJ, Durrant JD, Pierce LC, McCorvie TJ, Timson DJ, McCammon JA - Chem Biol Drug Des (2012)

Trajectory RMSD. Each dimer simulation was aligned to the first frame by minimizing the root-mean-square deviation (RMSD) of the Cα’s. RMSD was calculated using the first frame as a reference. For this plot, and in subsequent figures, apo is depicted in black, UDP-galactose in blue, UDP-glucose in red, and the UDP-ketose intermediate in brown. As each substrate was derived from UDP-galactose, the systems needed 9 nseconds to equilibrate (gray box). Trajectory analysis was performed on the subsequent 50 nseconds of each dimer simulation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3399956&req=5

fig02: Trajectory RMSD. Each dimer simulation was aligned to the first frame by minimizing the root-mean-square deviation (RMSD) of the Cα’s. RMSD was calculated using the first frame as a reference. For this plot, and in subsequent figures, apo is depicted in black, UDP-galactose in blue, UDP-glucose in red, and the UDP-ketose intermediate in brown. As each substrate was derived from UDP-galactose, the systems needed 9 nseconds to equilibrate (gray box). Trajectory analysis was performed on the subsequent 50 nseconds of each dimer simulation.
Mentions: Alpha carbon RMSD plots of each homodimer trajectory are shown in Figure 2. As the initial protein conformation of each system was that of the crystallographic UDP-galactose-bound state, the first 9 nseconds of each homodimer simulation were discarded to account for system equilibration. The remaining 50 nseconds of the dimeric simulation were used for subsequent analysis. In total, 400 nseconds of productive TbGalE monomer simulation were generated.

Bottom Line: As current drug treatments are either highly toxic or ineffective, novel trypanocides are urgently needed.The sampled conformations and protein dynamics depend not only on the presence of a UDP-sugar ligand, but also on the chirality of the UDP-sugar C4 atom.This dependence provides important insights into TbGalE function and may help guide future computer-aided drug discovery efforts targeting this protein.

View Article: PubMed Central - PubMed

Affiliation: Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, CA 92093-0365, USA. a1friedm@ucsd.edu

Show MeSH
Related in: MedlinePlus