Part I: Analyzing a research article: please obtain and read the article, "Screening of commercial cyclic peptide as inhibitor NS5 methyltransferase of Dengue virus through Molecular Docking and Molecular Dynamics Simulation", by Tambunan and co-authors. The article is freely available in the Journal "Bioinformation". After you read the article, answer the below questions.
1. What disease is the paper focused on and how many cases are there every year?
a. west Nile virus infection and 50-100 million
b. dengue infection and 5-10 million
c. dengue infection and 50-100 million
d. HIV infection and 50-100 million
2. The protein target the paper focused on is _______. It is ______ amino acids and is involved in ______ and DENV ________.
a. NS1, 800, RNA capping and genome replication
b. NS5, 900, RNA capping and genome replication
c. NS5, 900, DNA capping and genome replication
c. NS2B, 900, RNA capping and genome replication
3. The NS5 MTase domain is a promising target for drug inhibition because:
a. methylation is critical to the DENV life cycle and survival
b. acetylation is critical to DENV survival
c. methylation is not critical to the DENV life cycle and survival
d. de-methylation is critical to the DENV life cycle and survival
4. Two binding sites were targeted; they are:
a. SAM and SAH
b. SAH and RNA cap
c. SAM and RNA cap
d. RNA cap and DNA cap
5. What class of compound and how many were docked into the NS5 binding sites and what PDB structure was used?
a. cyclic nucleotides, 300, 2S41
b. cyclic non-peptidic small molecules, 300, 1P41
c. linear peptides, 300, 1YAH
d. cyclic peptides, 300, 2P41
e. cyclic peptides, 3000, 2P41
6. What computational work-flow was used in the study?
a. docking, ADME prediction and normal mode analysis
b. docking, ADME and toxicity prediction and conformational analysis
c. docking, ADME prediction and molecular dynamics
d. docking, ADME and toxicity prediction and molecular dynamics
7. The ligand with the best predicted binding affinity at the SAM site is
a. Atriopeptin I
b. TWY
c. SAH
d. Ser-Ala-SAP-IIB
e. Human urotensin
f. Tumor targeted pro-apoptotic peptide
g. none of the above
8. What primary biophysical criterion was used to identify four promising docked ligands for each binding site?
a. predicted binding affinities less than (more negative) standards
b. predicted binding affinities greater (more positive) than standards
c. experimental binding affinities less (more negative) than standards
d. experimental binding affinities greater (more positive) than standards
9. Is [Tyr123] Prepro Endothelin (110-130) predicted to have good ADME/Tox properties?
a. yes
b. no
10. The authors ultimately conclude that [Tyr123] Prepro Endothelin (110-130) is a promising inhibitor of DENV because:
a. it has a lower predicted binding affinity than standards, poor predicted ADME/Tox and is too expensive
b. it has a lower predicted binding affinity than standards, good predicted ADME/Tox and exhibited a stable MD trajectory
c. it has a lower predicted binding affinity than standards, good predicted ADME/Tox and exhibited an unstable MD trajectory
d. it has a higher predicted binding affinity than standards, good predicted ADME/Tox and exhibited an unstable MD trajectory
Part II: Multiple choice questions based on 2P41 structure. You will have to use SPDBV, VegaZZ and Vina to answer some of the questions.
11. In terms of secondary structure, the 2P41 structure is best classified as:
a. alpha-helical
b. beta
c. mixed alpha helical and beta
d. unstructured
12. Using SPDBV calculate the number of hydrogen bonds formed between the SAH ligand and the dengue methyltransferase protein.
a. 10
b. 2
c. 5
d. 7
e. 0
13. The SAH OXT atom forms a hydrogen bond with the N Trp87 atom. Calculate the approximate electrostatic energy of the SAH OXT atom interaction with N Trp85, assuming the interacting atoms are completely buried and are surrounded by "oily" groups. Use SPDBV to calculate the inter-atomic distance and the partial charge on Trp87 N; assume the partial charge on OXT is -0.55.
a. 16.23 kcal/mol
b. 0.21 kcal/mol
c. 4.06 kcal/mol
d. none of the above
14. Prior to a docking calculations, protein structures are sometimes "regularized" or energy "minimized". Regularization of a protein structure often involves setting all of the bond lengths and angles to their equilibrium values. Assuming the 2P41 protein structure has been perfectly "regularized", what would it's SPDBV molecular mechanics bond energy be?
a. > 0 kJ/mol
b. < 0 kJ/mol
c. = 0 kJ/mol
d. = 761.848 kJ/mol
15. The coordinates of the SAH C4' atom are:
a. -11.306, 86.124, 8.985
b. 86.124, -11.306, 8.985
c. -11.306, 86.124, 19.98
d. -11.217, 84.676, 9.419
16. Using the coordinates of the SAH C4' atom to define to SAH binding site, and using the SAH ligand from the 2P41 file, use Vina to re-dock SAH into its binding site. The predicted binding affinity for the best Vina pose is approximately:
a. -12.3 kcal/mol
b. -8.0 kcal/mol
c. -6.5 kcal/mol
d. -4.7 kcal/mol
e. none of the above
17. Calculate the inter-atomic distances between the SAH ligand x-ray coordinates and pose 1 predicted coordinates for N6-N6, C4'-C4', and carboxyl C-C. Based on these distances, calculate the approximate average distance deviation between pose 1 and the x-ray SAH ligand.
a. 3.3 Å
b. 0.15 Å
c. 2.2 Å
d. 1.1 Å.