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Refining the Structure of cADPR

Refining the Structure of cADPR. Rodney Agnant and Dr. Steven M. Graham Harlem Children Society and St. John’s University. ♠ Introduction ♠. What is cADPR?. cADPR – cyclic Adenosine Diphosphate Ribose…

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Refining the Structure of cADPR

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  1. Refining the Structure of cADPR Rodney Agnant and Dr. Steven M. Graham Harlem Children Society and St. John’s University

  2. ♠ Introduction ♠

  3. What is cADPR? • cADPR – cyclic Adenosine Diphosphate Ribose… • … is an organic molecule comprised of carbon, hydrogen, oxygen, nitrogen and phosphorus. • … contains both rings and chains that are able to move. • … is important for regulating calcium levels in cells; calcium regulates many cellular processes.

  4. ♠ Purpose & Hypothesis ♠ • Over 100 analogs of cADPR are known. • Does the precise structure (better conformation of cADPR determine its function-its ability to cause calcium release? • cADPR and its analogs have been characterized structurally only at a low level of sophistication. A thorough structure/function study requires a more rigorous approach to structure.

  5. cADPR: North and South Conformations North South R-ring R-ring A-ring A-ring

  6. Two Structure Analysis Programs • PSEUROT is a program that calculates H-H (“proton-proton”) angles and ribose ring angles. The input for Pseurot is H-H coupling data obtained from H Nuclear Magnetic Resonance (NMR) Spectroscopy. • HyperChem is a program that allows one to create and optimize molecular structures in silico. Hyperchem provides H-H and ribose ring angles that may not be obtainable from ‘H NMR data.

  7. ♠ Materials & Procedures ♠

  8. HyperChem Procedure • Twenty different conformations of cADPR were built and their structures optimized in HyperChem. • All fCCC/O and fHCCH were extractd from each structure. The plots of fCCC/O versus fHCCH were constructed

  9. PSEUROT Procedure fHCCH = A●fCCC/O + B JHCCH fHCCH = A●fCCC/O + B

  10. ♠ Results & Conclusion ♠

  11. Pseurot-Hyperchem Comparison Pseurot Our Hyperchem Default A,B A,B • 1’2’ 1.102, 123.3 1.079 124.4 • 2’3’ 1.090, 0.2 1.132-2.0 • 3,4’ 1.095-124.9 1.102-124.3 Output: Output: N(60º) : S(204º) N(68º) : A(210º) 31 : 69 32 : 68

  12. Conclusion & Future • When comparing results of Hyperchem derived A, B to default and PSEUROT A,B the discrepancy was minimal. • We can conclude that Hyperchem can be used to derive the parameters needed for Pseurot • Our future goals are to obtain and use molecules unknown to PSEUROT, for example 2’-dA cADPR.

  13. ♠ Acknowledgments♠ • Dr. Steven Graham • St John’s University Faculty and Staff • Dr. Sat Baccharaya • Harlem Children Society Staff

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