Abstract
BackgroundThree new analogs of berberine with aryl/arylalkyl amino carbonyl methyl substituent at the 9-position of the isoquinoline chromophore along with berberrubine were studied for their binding to tRNAphe by wide variety of biophysical techniques like spectrophotometry, spectrofluorimetry, circular dichroism, thermal melting, viscosity and isothermal titration calorimetry.Methodology/Principal FindingsScatchard binding isotherms revealed that the cooperative binding mode of berberine was propagated in the analogs also. Thermal melting studies showed that all the 9-O-N-aryl/arylalkyl amino carbonyl methyl substituted berberine analogs stabilized the tRNAphe more in comparison to berberine. Circular dichroism studies showed that these analogs perturbed the structure of tRNAphe more in comparison to berberine. Ferrocyanide quenching studies and viscosity results proved the intercalative binding mode of these analogs into the helical organization of tRNAphe. The binding was entropy driven for the analogs in sharp contrast to the enthalpy driven binding of berberine. The introduction of the aryl/arylalkyl amino carbonyl methyl substituent at the 9-position thus switched the enthalpy driven binding of berberine to entropy dominated binding. Salt and temperature dependent calorimetric studies established the involvement of multiple weak noncovalent interactions in the binding process.Conclusions/SignificanceThe results showed that 9-O-N-aryl/arylalkyl amino carbonyl methyl substituted berberine analogs exhibited almost ten folds higher binding affinity to tRNAphe compared to berberine whereas the binding of berberrubine was dramatically reduced by about twenty fold in comparison to berberine. The spacer length of the substitution at the 9-position of the isoquinoline chromophore appears to be critical in modulating the binding affinities towards tRNAphe.
Highlights
There has been a remarkable increase in our understanding of the critical roles played by RNA in a variety of structural, regulatory and enzymatic processes in the cells [1]
Conclusions/Significance: The results showed that 9-O-N-aryl/arylalkyl amino carbonyl methyl substituted berberine analogs exhibited almost ten folds higher binding affinity to tRNAphe compared to berberine whereas the binding of berberrubine was dramatically reduced by about twenty fold in comparison to berberine
Analog B1 exhibited absorption maxima at 328, 373 and 482 nm and in presence of increasing concentration of tRNA hypochromic changes were observed in its absorption spectra, but the extent of hypochromicity was significantly lower compared to BER and its 9-O-N-aryl/arylalkyl amino carbonyl methyl substituted analogs
Summary
There has been a remarkable increase in our understanding of the critical roles played by RNA in a variety of structural, regulatory and enzymatic processes in the cells [1]. TRNA is the small RNA chain consisting of 73–93 nucleotides transferring a specific amino acid to a growing polypeptide chain at the ribosomal site of protein synthesis during translation. It has a cloverleaf structure (Fig. 1A) that shows a high degree of folding stabilized by base stacking, base pairing and other tertiary interactions. It has a 39 terminal site for amino acid attachment which is catalyzed by an aminoacyl tRNA. Three new analogs of berberine with aryl/arylalkyl amino carbonyl methyl substituent at the 9-position of the isoquinoline chromophore along with berberrubine were studied for their binding to tRNAphe by wide variety of biophysical techniques like spectrophotometry, spectrofluorimetry, circular dichroism, thermal melting, viscosity and isothermal titration calorimetry
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