BIRLA INSTITUTE OF TECHNOLOGY AND SCIENCE, PILANI

K K Birla Goa Campus, Zuarinagar, Goa 403726

Comprehensive Examination, 9th May 2018
Course No.: BIO F417 Title: Biomolecular Modeling
Answer All Questions. Total Marks: 40 Duration: 3 Hours
There are a total of nine questions totaling to 40 marks. Please read the instructions for each
question carefully. Please don’t spend too much time on any one question. Please write clearly and
legibly.

Q1. The left panel shows a substrate bound in the active site of the enzyme that is responsible for the
synthesis of phenylalanine in plants. This enzyme is readily inhibited by 'Round-up', a widely used
herbicide. The bound substrate is shown in thick lines and labeled with 'S' and residues that belong to the
enzyme are shown in thin lines. The right panel shows a mutant enzyme that has been isolated from
plants that are resistant to 'Round-up'. The structure of Round-up is shown to the far right.

Wild-Type Mutant
O O

+ +
H3N NH H3N NH

OO OO
P O
O O P O
O O P
O
H O H O N O

S H O +
S H O CH3 O
NH3 Round-up
S

O
N
N H
H O

(A) How does the mutant enzyme differ from the wild-type enzyme? [2]
(B) What type of inhibitor is Round-up, a competitive one or a non-competitive inhibitor? Justify
your answer with reference to the chemical structure of Round-up. [1]
(C) Round-up binds poorly to the mutant enzyme. How might you modify Round-up such that it will
become a more effective inhibitor of the mutant enzyme and be able to kill the plant? [2]
Q2. Describe the kinds of interactions that are be involved in stabilizing folded protein structures. [3]

Q3. How to identify protein-protein interface residues? [2]

Q4. elNémo is the Web-interface to the Elastic Network Models (ENMs), a fast and simple way for
computing the low frequency normal modes of a macromolecule.

(A) Define ‘collectivity’ and ‘overlap’. (B) Write applications of coarse-grained ENMs. [2+1]
Q5. FireDock is an efficient method for refinement and re-scoring of rigid-body protein-protein docking
solutions. Draw flowchart for FireDock. [3]

Q6. (A) How good can comparative modeling be? (B) What are the uses of comparative models? [2 + 2]

Q7. “Structure based drug design” is the method of choice for many of the pharmaceutical companies in
the last three to four decades. Please answer the following (The answer should preferably be in a flow chart
mode): [3+2]
(A) Using an example of your choice, please describe the various steps involved in “rational drug
design”. Please also mention the limitations/improvements required at each of these steps.
(B) What is the role of “bioinformatics” and “Chemoinformatics” in overcoming the limitations
mentioned in your answer to part (A).

Q8. (A) What are Lipinski’s rules? Calculate the molecular weight, number of H-bond donors and H-
bond acceptors in each of the molecules given below? Comment on whether these molecules follow
Lipinski’s rule [Please ignore log(P) in giving your answer]. [8]

(a) Paracetamol (b) Lovastatin (c) Rosiglitazone (d) Cetirizine

(B) What does the log partition coefficient (logP) of a compound indicate? How does one measure
the logP value of a compound experimentally? What computational methods are available to predict logP
value of a compound? [3]

Q9. Shown below is the SMILES notation for Promethazine, a neuroleptic medication to reduce
restlessness, nervousness, and agitation caused by psychiatric conditions. Please convert the SMILES
notation to 2D covalent structure. [4]

S2c1ccccc1N(c3c2cccc3)CC(N(C)C)C

***** Happy Molecular Modeling and Summer Break *****