sb wh tn jk vit c quantum presentation1
TRANSCRIPT
Vitamin C: DFT Analysis and Optimization of its Function as a Cofactor in Collagen Synthesis
By Shelby Burns, Will Henry, Jacob Kordsmeier, and Tyrus Nelson
Monday Group
OUTLINE
• Importance of Vitamin C• Basis Sets Explanation &
Utilized– CCPVDZ
• B3LYP• BPV86• LSDA
– CCPVTZ• B3LYP• BPV86• LSDA
– 631-G• B3LYP• BPV86• LSDA
• Methods– Gaussian Program– Bond Length
Measuring • Results
– Opt-Vit C– 2JIG– Bond Length %Error
• Conclusion
THE PURPOSE OF OUR EXPERIMENT
• To deduce and optimize how Vitamin C binds within the active site of prolyl-4-hydroxylase which is necessary for collagen synthesis
• Also to explore and compare advanced DFT basis and functional sets.
IMPORTANCE OF VITAMIN C
• Required Cofactor in collagen synthesis.• Collagen forms 25-35% of the human body protein.• Prolyl-4-hydroxylase catalyzes one step of the
formation of collagen. • Low levels of Vitamin C lead to scurvy.
Prolyl-4-hydroxylase
BIOCHEMICAL ANALYSIS
• Prolyl-4-hydroxylase X-ray diffraction crystal structure at 1.85Å.
• Vitamin C is an activator. • In order to crystalize the protein, the
inhibitory ligand, pyridine dicarboxylate, was used.
• We analyzed this ligand’s bonding pattern and superimposed Vitamin C.
• Hydrogen bonding, dipole-dipole, and Van der Waals forces hold the ligand.
• Hydrogen Bonds: Asp145, Trp243, Thr241, Thr178, Tyr134, Lys137.
• Van der Waals forces: Ser229, Gly228, His227, His134, Leu166.
DENSITY FUNCTIONAL THEORY (DFT)
• What is DFT?• Quantum Mechanical Modeling Method• Based on electron density• Basis Sets we used: cc-PVTZ, cc-PVDZ, 6-31G• Functionals we used: B3LYP, BPV86, LSDA
DATA
Optimized Vitamin C Image Analysis
– CCPVDZ• B3LYP• BPV86• LSDA
– CCPVTZ• B3LYP• BPV86• LSDA
– 631-G• B3LYP• BPV86• LSDA
Optimized Vitamin C in prolyl 4-hydroxylase• Opt-Vit C with Labled Amino
Acids• Prolyl 4-hydroxylase structure
OPTIMIZED 6-31G
6-31G B3LYP6- 31G BPV86
178.18˚179.67˚
178.00˚
1.224 Å
1.22 Å
1.21 Å
6-31G LSDA
Avg Angle ~ 178.61˚Avg Bond ~ 1.22Å
OPTIMIZED CCPVDZ
CCPVDZ B3LYP
CCPVDZ LSDA
CCPVDZ BPV86
178.65˚178.01˚
179.99˚
1.198 Å
1.198 Å1.224 Å
Avg Angle ~ 178.49˚Avg Bond ~ 1.22Å
OPTIMIZED CCPVTZ
CCPVTZ B3LYP CCPVTZ BPV86
CCPVDZ LSDA
170.81˚ 178.37˚
178.10˚
1.198 Å
1.22 Å
1.224 Å
Avg Angle ~ 175.76˚Avg Bond ~ 1.22Å
PYRIDINE DICARBOXYLATE IN POCKET HYDROGEN BONDS ONLY
A.ASP145
A.TRP243
A.LYS237
A.TYR134
A.THR178
A.THR241
Hydrogen Bond Avg ~ 3.3 Å
A.THR178
A.TRP243
A.ASP145
Vitamin C CCPVDZ
A.LYS237
A.TYR134
OPTIMIZED VIT C SUPERIMPOSED ON PROLYL 4-HYDROXYLASE HYDROGEN ONLY
A.THR178
A.THR241
Hydrogen Bond Avg 4.1 Å
PYRIDINE DICARBOXYLATE-HYDROGEN BONDING ONLY
CALCULATIONS OF HYDROGEN BOND DISTANCE ERROR ON 2JIG AND OPT-VITC
Amino Acid Residues PDB Bond Lengths (Å) Exp. Bond Length Opt-VitC (Å) % Error
A.THR241 2.7 5.9 117.78
A.TRP243 3.3 3.6 8.18
A.ASP145 3.0 2.1 31.33
A.TYP134 3.0 2.4 21.33
A.THR178 2.7 5.3 97.04
A.LYS237 2.7 5.3 95.93
PYRIDINE DICARBOXYLATE IN POCKET VAN DER WALLS FORCES A.ASP145
A.TRP243
A.LYS237
A.TYR134A.THR178
A.THR241
A.GLY228A.HIS227
A.HIS143
A.LEU166
A.SER229
Van der Waals Avg~3.9 Å
A.ASP145
A.TRP243
A.LYS237
A.TYR134A.THR178
A.THR241
A.GLY228A.HIS227
A.HIS143
A.LEU166
OPTIMIZATION VIT C IN POCKETVAN DER WALLS FORCES
A.SER229
Van der Waals Avg~4.1Å
PYRIDINE DICARBOXYLATE IN POCKET VAN DER WALLS FORCES
DATA TABLE
Amino Acid Residues PDB Bond Lengths (Å) Exp. Bond Length Opt-VitC (Å) % Error
A.HIS143 3.3 3.25 1.52
A.HIS227 3.0 2.23 25.7
A.GLY228 3.9 5.7 46.2
A.GLY228 3.5 5.35 44.6
A.SER229 3.7 4.07 13.1
A.LEU166 3.6 4.19 16.4
A.LEU166 3.7 3.47 6.22
A.TRP243 3.8 4.2 10.5
HYDROGEN & VAN DER WAALS PYRIDINE DICARBOXYLATE A.ASP145
A.TRP243
A.LYS237
A.TYR134A.THR178
A.THR241
A.ASP145
A.GLY228A.HIS227
A.HIS143
A.LEU166
A.SER229
A.ASP145
A.TRP243
A.LYS237
A.TYR134
A.THR178A.THR241
A.GLY228A.HIS227
A.HIS143
A.LEU166
A.SER229
HYDROGEN & VAN DER WAALS OPT-VITAMIN C
AcknowledgementsDr. IsomUniversity of Central Arkansas
Work Cited
• (2007).J.BIOL.CHEM.282:37112