Transition State of a Creatine Molecule during Dehydration

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Transition State of a Creatine Molecule during
Dehydration

• Computation Chemistry Seminar 2000
• Ravi Agarwal
• John ODowd

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Purpose

• The purpose of our project was to determine the
  transition state of the dehydration of creatine
  into creatinine. This reaction was chosen
  because of our interest in creatine as a body
  supplement in the body.

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Background Information

• Creatine is an amino acid (a protein) that is
  produced in tiny doses by the liver, kidneys and
  pancreas and stored in the muscles. In food, it
  is found in meat and fish.
• Creatine is the guanidine- derived,
  phosphorylated compound which maintains cellular
  ATP homeostasis in the higher animals.
• Creatine is also a body supplement used to
  increase anaerobic performance.

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Background Information

• Creatine helps the body replenish energy through
  the reaction of creatine monohydrate to creatine
  phosphate.
• Energy in the muscles comes from the reaction of
  adenosine triphosphate to adenosine diphosphate
  (ATP ADP). Creatine helps replenish energy by
  donating its phosphate back to ADP so the process
  can repeat.

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Background Information

• Creatinine is the dehydrated form of creatine.
  Its significance bio-chemically is that creatine
  cannot be excreted from the body. So the body
  dehydrates it and then excretes creatinine.

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Dehydration of Creatine
NH2
NH
C
C
CH3
CH3
NH
NH
N
N
O
CH2
CH2
H20
C--O
C
OH
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Computation Approach

• The experiment began with the use of MacSpartan
  on a Power Macintosh. We completed our project
  using MacSpartan Pro.
• The transition state was determined using the
  Semi-Empirical method of AM-1.
• Due to the complexity of our molecule, the ab
  initio method (321G) was impractical. We used
  the Semi Empirical method (AM-1) for all of
  calculations.

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Computation Approach

• First we built the creatine molecule in
  MacSpartan Pro. Then we ran a geometry
  optimization using the AM-1 basis set. Using our
  predictions, we used the transition search by
  editing the bonds so that the creatinine is
  formed.

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Transition Search Approach
The nitrogen bonds to the carbonyl.
The OH group bonded to the carbon will attack
the hydrogen bonded to the NH2
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Computational Approach

• Then we ran a transition search for our
  prediction.
• In order to determine if the molecule was a true
  transition state it must have one unique
  imaginary frequency.
• After the frequency scan, our transition search
  was determined to be a true transition state for
  the dehydration of creatine.
• This molecule is the transition state.

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Transition State
Moving hydrogen
Nitrogen bonded to carbonyl.
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Transition State

• Has one imaginary frequency.
• Follows our prediction
• Nitrogen bonded to carbonyl
• Hydrogen on the amine moves from to the hydroxyl
  to form water.
• Calculated single point energies to determine
  activation energy using AM-1 basis set.

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Optimized Transition State

• Transition State was optimized using AM-1 basis
  set.

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Single Point Energies
7.618 kcal/mol
5.287 kcal/mol
Transition
Creatinine
Activation Energy 70.576 kcal/mol
Creatine
-62.958 kcal/mol
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Conclusion

• Found transition state for dehydration of
  creatine based on one imaginary frequency when we
  scanned the transition structure.
• Calculated Single Point Energies to determine
  activation energy. Activation energy is large so
  an enzyme most likely catalyzes the reaction.