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 KEY

Mutant
O
Q1. (A) The polar and charged Lysine sidechain has been replaced by the
non-polar sidechain of Methionine. +
NH
H3N
(B) Competitive inhibitor : Round-up is structurally very similar to the true O
O
P
substrate, with a negatively charged phosphate at one end and a carboxylic O
N CH3
acid group at the other.
Round-up CH3
(C) The reason Round-up binds poorly to the mutant enzyme is the
unfavorable interaction between the polar/charged carboxylic acid group CH3
and the Methionine side-chain. If this was changed to a non-polar group, S
this would result in favourable van der Waals interaction as well as a
favorable hydrophobic effect. One possibility is shown to the right. O
N
(Note: Methionine does NOT form disulfide bonds, only Cysteine can.) H

Q2. Noncovalent interactions, including :

- hydrogen bonding between polar side chains, e.g., Ser and Arg
- hydrophobic interaction between nonpolar side chains, e.g., Val and Ile
- electrostatic attraction between side chains of opposite charge, e.g., Lys and Glu
- electrostatic repulsion between side chains of like charge, e.g., Lys and Arg, Glu and Asp
Covalent interactions : Disulfide (-S-S-) bonds between side chains of cysteines

Q3. Atom Nucleus Distance; Atom Van der Waals Radii Distance; ASA Change on Complexation.

Q4. (A) Collectivity : The degree of collectivity measures the collective protein motion in the mode
considered, i.e., the number of atoms which are significantly affected in the normal mode. The
conformational change is maximally collective for a value of one. On opposite, for local motion, where the
conformational change involves only few atoms.
Overlap : The overlap measures the degree of similarity between the direction of a chosen conformational
change and the one given by the normal mode considered. A value of one for the overlap means that the
direction given by the normal mode considered is identical with the conformational change.
(B) Coarse-grained ENMs have been widely used to solve a variety of biological problems including
functional motions of protein complexes, ligand binding mechanism, refinement of low resolution structural
data, and transition pathway generation.

Q5.
Q6. (A) Model quality depends on various factors, e.g., template(s) selection, quality of the template(s),
query-template(s) alignment. (B) Applications (depends on model quality): identify patches of conserved
surface residues; functional relationships from structural similarity; structure from sparse experimental
restrains; etc.
Q7. Please refer to the “drug design” lecture slides for the answers for both parts.

Q8. (A) All the molecules follow the Lipinski’s rules

(B) The ability of a molecule to pass through a lipophilic cell membrane. An Octanol-Water phase
partition experiment is used to determine the logP. ClogP and AlogP are the computational prediction
model available.

Q9.

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