Molecular Modeling

Alex Strube

In this assignment, I downloaded a model of a protein-heterocompound complex involving aspirin as the heterocompound, in .pdb format, from RCSB PDB, a protein database. I extracted the model of the complexed aspirin from the larger model of the complex using DS Visualizer software. It is displayed as Figure 1.

Fig. 1: Ball and Stick model of aspirin (AIN)

Figure 2 is a Lewis structure of aspirin drawn by me using ChemSketch software. It includes free pairs of electrons.

Fig. 2: Lewis structure of aspirin (AIN)

Figure 3 is the complex, with the protein part displayed as solid ribbons. The oxygens in the heterocompound are red.

Fig. 3: Complex formed between group II phospholipase A2 (1tgm) and aspirin (AIN).

PART 2

Table shows steric energy values for aspirin in the conformation in which it complexes with 1tgm compared to its minimum energy conformation. The value for total steric energy for the original conformation was 29.9479 kJ/mol; The value for total steric energy for the minimized conformation was 8.0763 kJ/mol. For stretch energy, which represents the energy associated with any bonds that are distorted from their optimal length, the value for the original conformation was higher than the value for the minimized conformation. For bend energy, which represents the energy associated with any bond angles that are deformed from their optimal values, the value for the original conformation was higher than the value for the minimized conformation. For stretch-bend energy, which represents the energy required to stretch the two bonds involved in a bond angle when that bond angle is severely compressed, the value for the original conformation was higher than the value for the minimized conformation. For torsion energy, which represents the energy associated with deforming torsional angles (dihedral angles) in the molecule from their ideal values, the value for the original conformation was higher than the value for the minimized conformation was. For Non-1, 4 van der Waals energy, which represents the energy for the through-space interaction between pairs of atoms that are separated by more than three atoms, the value for the original conformation was lower than the value for the minimized conformation was. For 1, 4 van der Waals energy, which represents the energy for the through-space (non-bonded) interaction of atoms separated by two atoms, the value for the original conformation was lower than the value for the minimized conformation was. For dipole/dipole energy, which represents the energy associated with the interaction of bond dipoles, the value for the original conformation was lower than the value for the minimized conformation was.

Fig. 6: The original heterocompound conformation superimposed with the energy minimized conformation.

The original heterocompound conformation was superimposed with the energy minimized conformation using the overlay function of Chem3D Ultra. Use this function by going to View | Model Explorer: A pane identifying the each molecule in the active window as fragments will open. Choose one fragment using Structure | Overlay | Set Target Fragment. Select the other fragment and choose Structure | Overlay | Fast Overlay. The molecules will be superimposed.

Except for a few hydrogen atoms, the atoms of the two conformations all partially overlap. Perhaps this means the original conformation was already at a low energy.

PART 3

Fig. 7: Primary structure of 1tgm.

Fig. 8: Ligplot for AIN.

Fig.8: Ligand Interactions with Certain Amino Acids on 1tgm.

Fig.9: Ribbon Model of 1tgm Showing Legend Interactions with Certain Amino Acids on 1tgm.

Figure 7 shows the primary structure of Phospholipase A2, also known by the PDB ID: 1tgm. Each letter represents an amino acid; the red dots over some letters indicate ligand interactions.

Figures 8, 9, and 10 show the interaction between aspirin and three amino acid residues, Leu 2, Ala 18, and Ile 19, in the Phospholipase A2 protein. Figure 8 is a LigPlot. The “eyelashes” in figure 8 indicate hydrophobic interactions between these amino acid residues in the protein and the heterocompound aspirin.

PART 4

Amino acid residue & position #	Atoms in hetero that interact	!interaction
LEU 2	C8 & C9	hydrophobic
ALA 18	C4, C3, C7, O1 & O2	hydrophobic
ILE 19	C4, C3, C7, O1 & O2	hydrophobic

Table 2: Amino Acid Residue Interactions.

Table 2 lists the amino acid residues in 1tgm that interact with the complexed heterocompound aspirin, their positions in the protein’s primary structure, which atoms they interact with in the heterocompound, and what type of interaction (hydrogen bond or hydrophobic) the LigPlot indicates.

References:

1. RCSB. “1tgm.” RCSB PDB: Structure Explorer. Dec. 2, 2008. http://www.rcsb.org/pdb/explore/explore.do?structureId=1TGM

2.Singh, N., Jabeen, T., Sharma, S., Bhushan, A., Singh, T.P. Crystal structure of a complex formed between group II phospholipase A2 and aspirin at 1.86 A resolution To be Published. Similar published article link: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=2pws&template=main.html.

3. PDBSum. “Ligand/Metal Interactions: 1tgm.” http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=1tgm&template=ligands.html&l=1.1