Partial Atomic Charges MM Force Field Parameterization

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AMBER Parameters for Pseudouridine
Delon Wilson Advisor J. SantaLucia
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Outline

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

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Nucleic Acid Structure
Phosphate
G,C,A,T (DNA) G,C,A,U (RNA)
Base
Sugar
Deoxyribose (DNA) Ribose (RNA)
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PSU and Modified NAs

• 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

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PSU and Modified NAs

• 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)

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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

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Molecular Mechanics

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

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Potential Energy Model

• The force field energy
• where

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Pseudouridine
Psu
Base joined to ribose via C-C, Vs. C-N in regular
NAs
Uridine
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Starting structure from PDB
Perform Geometry Optimization (HF-631G)
Compute Electrostatic Potential Charges (popmk)
Fit ESP charges (RESP)
MD simulation (AMBER)
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Initial Structure
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Gaussian Keywords

• p hf 6/31-g(d) opt popmk geomconnectivity test
  iop(6/332)
• Duration around 5hrs

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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

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Calculation of ESP/MEP

• Calculate approximate ? from eq geom
• Calculate e density from psi
• The ESP at point 1 is

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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 ?

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Results
Partial charges on pseudouridine values in
parenthesis from Amber website, std0.23
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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.

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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).

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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

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Questions etc
Thank you