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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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Presentation Transcript
slide1

AMBER Parameters for

Pseudouridine

Delon Wilson

Advisor: J. SantaLucia

outline
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
Nucleic Acid Structure

Phosphate

G,C,A,T (DNA)

G,C,A,U (RNA)

Base

Sugar

Deoxyribose (DNA)

Ribose (RNA)

psu and modified na s
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
psu and modified na s5
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)
molecular mechanics
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
molecular mechanics7
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

potential energy model
Potential Energy Model

The force field energy

where

pseudouridine
Pseudouridine

Psu

Base joined to ribose via C-C,

Vs. C-N in regular NA’s

Uridine

slide10

Starting structure from PDB

Perform

Geometry Optimization (HF-631G*)

Compute

Electrostatic Potential Charges

(pop=mk)

Fit ESP charges

(RESP)

MD simulation (AMBER)

gaussian keywords
Gaussian Keywords
  • #p hf 6/31-g(d) opt pop=mk geom=connectivity test iop(6/33=2)
  • Duration: around 5hrs
esp some common methods
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
calculation of esp mep
Calculate approximate Ψfrom eq geom

Calculate e density from psi

The ESP at point 1 is:

Calculation of ESP/MEP
slide16
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 
results

.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

results18
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.
to do
…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).
references acknowlegment
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