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Interfacing medicinal chemistry with structural bioinformatics: implications for T box riboswitch RNA drug discovery.

Jentzsch F, Hines JV - BMC Bioinformatics (2012)

Bottom Line: Knowledge of the thermodynamic stability difference between two competing structural elements within the riboswitch, the terminator and the antiterminator, is critical for effective T box-targeted drug discovery.The ΔG of aminoacyl tRNA synthetase (aaRS) T box riboswitch terminators and antiterminators was predicted using DINAMelt and the resulting ΔΔG (ΔG Terminator - ΔG Antiterminator) values were compared.Average ΔΔG values did not differ significantly between the bacterial species analyzed, but there were significant differences based on the type of aaRS.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Chemistry, Leipzig University, Leipzig, Germany.

ABSTRACT

Background: The T box riboswitch controls bacterial transcription by structurally responding to tRNA aminoacylation charging ratios. Knowledge of the thermodynamic stability difference between two competing structural elements within the riboswitch, the terminator and the antiterminator, is critical for effective T box-targeted drug discovery.

Methods: The ΔG of aminoacyl tRNA synthetase (aaRS) T box riboswitch terminators and antiterminators was predicted using DINAMelt and the resulting ΔΔG (ΔG Terminator - ΔG Antiterminator) values were compared.

Results: Average ΔΔG values did not differ significantly between the bacterial species analyzed, but there were significant differences based on the type of aaRS.

Conclusions: The data indicate that, of the bacteria studied, there is little potential for drug targeting based on overall bacteria-specific thermodynamic differences of the T box antiterminator vs. terminator stability, but that aaRS-specific thermodynamic differences could possibly be exploited for designing drug specificity.

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Average calculated ΔΔG. Average calculated aaRS ΔΔG values grouped by a) bacteria and b) aaRS. Standard deviation indicated by bar and number of aaRS sequences averaged noted over the individual columns.
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Figure 3: Average calculated ΔΔG. Average calculated aaRS ΔΔG values grouped by a) bacteria and b) aaRS. Standard deviation indicated by bar and number of aaRS sequences averaged noted over the individual columns.

Mentions: The free energy values for the antiterminator and terminator structural elements of the T box genes analyzed were calculated using the DINAMelt webserver [21]. The predicted ΔG values are listed in Additional File 1 and the relative comparisons of terminator vs.antiterminator stability (ΔΔG) are summarized in Figure 3. The overall average ΔΔG for all aaRS studied was -12.8 kcal/mol. The average ΔΔG values did not differ significantly between bacteria when comparing between the pathogenic bacteria nor between pathogenic vs. the non-pathogenic bacteria studied (BS) (Figure 3a). In contrast, there were significant differences in ΔΔG averages between specific aaRS with alanyl aaRS having the smallest average ΔG (-7.8 ± 3.5 kcal/mol) and glycyl aaRS having the largest (-20.1 ± 4.6 kcal/mol) (Figure 3b). Based on these results, the glycyl aaRS, on average, may be best able to accommodate ligand-induced stabilization of the antiterminator and still allow formation of the terminator. An important factor to consider, however, is that the free energy calculations are based on empirically-derived parameters for known RNA structural motifs [21]. Structural motifs, especially in loops and bulges, that have not been previously characterized might contribute to the stability of the RNA elements and not be accounted for in the DINAMelt ΔG calculations. Since the loop of the antiterminator is not highly conserved [4], most likely there is no structural motif within it that might contribute to the antiterminator stability, however, the possibility cannot be excluded. Further investigation of experimentally-derived free energy values of individual antiterminators and terminators is needed.


Interfacing medicinal chemistry with structural bioinformatics: implications for T box riboswitch RNA drug discovery.

Jentzsch F, Hines JV - BMC Bioinformatics (2012)

Average calculated ΔΔG. Average calculated aaRS ΔΔG values grouped by a) bacteria and b) aaRS. Standard deviation indicated by bar and number of aaRS sequences averaged noted over the individual columns.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3375634&req=5

Figure 3: Average calculated ΔΔG. Average calculated aaRS ΔΔG values grouped by a) bacteria and b) aaRS. Standard deviation indicated by bar and number of aaRS sequences averaged noted over the individual columns.
Mentions: The free energy values for the antiterminator and terminator structural elements of the T box genes analyzed were calculated using the DINAMelt webserver [21]. The predicted ΔG values are listed in Additional File 1 and the relative comparisons of terminator vs.antiterminator stability (ΔΔG) are summarized in Figure 3. The overall average ΔΔG for all aaRS studied was -12.8 kcal/mol. The average ΔΔG values did not differ significantly between bacteria when comparing between the pathogenic bacteria nor between pathogenic vs. the non-pathogenic bacteria studied (BS) (Figure 3a). In contrast, there were significant differences in ΔΔG averages between specific aaRS with alanyl aaRS having the smallest average ΔG (-7.8 ± 3.5 kcal/mol) and glycyl aaRS having the largest (-20.1 ± 4.6 kcal/mol) (Figure 3b). Based on these results, the glycyl aaRS, on average, may be best able to accommodate ligand-induced stabilization of the antiterminator and still allow formation of the terminator. An important factor to consider, however, is that the free energy calculations are based on empirically-derived parameters for known RNA structural motifs [21]. Structural motifs, especially in loops and bulges, that have not been previously characterized might contribute to the stability of the RNA elements and not be accounted for in the DINAMelt ΔG calculations. Since the loop of the antiterminator is not highly conserved [4], most likely there is no structural motif within it that might contribute to the antiterminator stability, however, the possibility cannot be excluded. Further investigation of experimentally-derived free energy values of individual antiterminators and terminators is needed.

Bottom Line: Knowledge of the thermodynamic stability difference between two competing structural elements within the riboswitch, the terminator and the antiterminator, is critical for effective T box-targeted drug discovery.The ΔG of aminoacyl tRNA synthetase (aaRS) T box riboswitch terminators and antiterminators was predicted using DINAMelt and the resulting ΔΔG (ΔG Terminator - ΔG Antiterminator) values were compared.Average ΔΔG values did not differ significantly between the bacterial species analyzed, but there were significant differences based on the type of aaRS.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Chemistry, Leipzig University, Leipzig, Germany.

ABSTRACT

Background: The T box riboswitch controls bacterial transcription by structurally responding to tRNA aminoacylation charging ratios. Knowledge of the thermodynamic stability difference between two competing structural elements within the riboswitch, the terminator and the antiterminator, is critical for effective T box-targeted drug discovery.

Methods: The ΔG of aminoacyl tRNA synthetase (aaRS) T box riboswitch terminators and antiterminators was predicted using DINAMelt and the resulting ΔΔG (ΔG Terminator - ΔG Antiterminator) values were compared.

Results: Average ΔΔG values did not differ significantly between the bacterial species analyzed, but there were significant differences based on the type of aaRS.

Conclusions: The data indicate that, of the bacteria studied, there is little potential for drug targeting based on overall bacteria-specific thermodynamic differences of the T box antiterminator vs. terminator stability, but that aaRS-specific thermodynamic differences could possibly be exploited for designing drug specificity.

Show MeSH