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AMBER Parameters for Pseudouridine

AMBER Parameters for Pseudouridine. Delon Wilson Advisor: J. SantaLucia. Outline. Introduction and Motivation Pseudouridine & Modified Nucleic Acids Atomic charge in MM RESP/ Method The MEP Charge Fitting with Restraints Results Conclusion. Nucleic Acid Structure. Phosphate.

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AMBER Parameters for Pseudouridine

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  1. AMBER Parameters for Pseudouridine Delon Wilson Advisor: J. SantaLucia

  2. Outline • Introduction and Motivation • Pseudouridine & Modified Nucleic Acids • Atomic charge in MM • RESP/ Method • The MEP • Charge Fitting with Restraints • Results • Conclusion

  3. Nucleic Acid Structure Phosphate G,C,A,T (DNA) G,C,A,U (RNA) Base Sugar Deoxyribose (DNA) Ribose (RNA)

  4. PSU and Modified NA’s • Found as natural substances or obtained synthetically • Pseudouridine – 1% in rRNA, tRNA • produced by chemically modifiying one of the four bases (G, C, A, and T in DNA or U in RNA) • Important in biochemical regulation • Used extensively in chemistry, biochemistry, and pharmacology as probes to study biological mechanisms

  5. PSU and Modified NA’s • Major cause of spontaneous mutation in E. coli results from the presence of an unusual base in the DNA. e.g. 5-MethylCytosine • Successful applications as antibiotics or chemotherapeutic agents • e.g. AZT interferes with the replication of HIV (Human Immunodeficiency Virus)

  6. Molecular Mechanics • Modeling of biological systems • Accurate representation of electrostatic interactions crucial for force field application • Suitable force field parameters required for molecular mechanics and dynamics • force constants, atom types, bond distances, atomic charges

  7. Molecular Mechanics Amber: A suited of programs developed by Peter Kollman & Coworkers at UCSF Force field referred to by same name Parameters for regular NA’s (A,C,T,G,U) developed Suitable parameters for modified NA’s not available An albatross to computations for systems involving substantial amounts of mod. NA’s

  8. Potential Energy Model The force field energy where

  9. Pseudouridine Psu Base joined to ribose via C-C, Vs. C-N in regular NA’s Uridine

  10. Starting structure from PDB Perform Geometry Optimization (HF-631G*) Compute Electrostatic Potential Charges (pop=mk) Fit ESP charges (RESP) MD simulation (AMBER)

  11. Initial Structure

  12. Gaussian Keywords • #p hf 6/31-g(d) opt pop=mk geom=connectivity test iop(6/33=2) • Duration: around 5hrs

  13. ESP: Some Common Methods • Mulliken Population Analysis-does not reproduce ESP closely enough • Natural Population Analysis` • ESP derived using CHelpG scheme • ESP derived using MKS scheme

  14. Calculate approximate Ψfrom eq geom Calculate e density from psi The ESP at point 1 is: Calculation of ESP/MEP

  15. RESP • Least squares algorithm derives atom centered charges that best reproduces MEP • Potential calculated on large number of points on 4 shells of surfaces defined by {1.4, 1.6, 1.8, 2.0} x VDW radii • ESP at each point derived from QM 

  16. .4312 (.4295) .0748 (.0679) -.6135 (-.6223) .3418 (.4311) .0748 (.0679) .2104 (.1226) .0264 (.0558) .0788 (.1065) -.3604 (-.3548) -.3407 (-.6770) -.0759 (.3896) .1171 (.1174) -.5841 (-.6096) .0303 (-.1081) .5173 (.9290) .0461 (.0615) -.6271 (-.6541) -.2671 (-.7255) .2808 (.2022) .0069 (-.5317) .0736 (.0670) .3885 (.4376) .1714 (.2405) .3402 (.3859) .3842 (.8922) .0974 (.0972) .4098 (.4186) -.5962 (-.6139) -.5332 (-.6230) Results Partial charges on pseudouridine: values in parenthesis from Amber website, std=0.23

  17. Results • Calculations performed on a single Pentium IV processor. • Average CPU time to perform the geometry optimization of each nucleoside in the order of several hours (~5) • Charges for each ribonucleotide are in a good agreement with AMBER standard reference file (all_nuc94.in). • Calculations on pseudouridine deviate more than expected from the contributed values provided at the AMBER website.

  18. …To do • Investigate the dependence of the charges on conformation • Determine force field parameters for all (~103) of the naturally occurring modified nucleotides that occur in RNA and DNA. • Extend the AMBER force field so that nuclei acids with modifications may be routinely modeled. • Develop a novel force field specifically tailored to nucleic acid applications (NA_FF).

  19. References/Acknowlegment • U. C. Singh and P. A. Kollman J. Comp. Chem. vol.5, no.2, 129-145 (1984) • B.H. Besler, K.M. Merz Jr., and P.A. Kollman J. Comp. Chem. vol.11, no.4, 431-439(1990) • JSL Lab • Schlegel Lab

  20. Questions etc… Thank you

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