Write

 the  number  assigned  to  you  here:  

Written exam in Molecular Modeling

Stockholm University
January 19, 2013 9:00-14:00

Instructions
Allowed tools: paper, pen, and dictionary


Write your anonymous code on ALL pages
.

Grades will be based on total score (80 from the exam, 20 from the projects
plus potential bonus from the lab reports):

A 92-100
B 80-91
C 68-79
D 56-67
E 50-55
Fx 45-49
F 0-44

Please answer each of the 15 questions within the provided space, so we can
split the pages when correcting the exam. If you need more space, just write
on the back of the same sheet.

 You may answer in English or Swedish.



Good luck!

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Write  the  number  assigned  to  you  here:  

1. Give an example of (i) a clearly hydrophobic and (ii) a clearly

hydrophilic amino acid. Where in a protein do you expect to find these
two amino acids? Also, why does a protein’s structure depend on the
pH of the solution? (5p)

2. How does the conjugate gradient method differ from the steepest
descent method? (3p)

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Write  the  number  assigned  to  you  here:  

3. Today there are structures of G protein-coupled receptors (GPCRs)

in both inactive and active conformations. However, just a few years
ago, there was only one inactive structure of Rhodopsin available. At
that time, how would you have tried to predict the structure of the active
state with computational tools? Note: The activation of a GPCR is a
“slow” process, in the order of milliseconds, i.e. a typical atomistic
molecular dynamics simulation will not work. (3p)

4. Describe two techniques used to reduce computational time for

molecular dynamics simulations. (5p)

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5. How is temperature controlled in molecular dynamics and Monte

Carlo simulations? (4p)

6. Describe the three types of scoring functions that are used in

molecular docking. (6p)

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7. Two sampling algorithms used in molecular docking programs are

incremental construction (“Anchor and grow”) and genetic algorithms.
Describe any one of these approaches. (5p)

8. Describe two strategies that can be used to assess the accuracy of a

molecular docking program. (4p)

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9. Briefly describe how pharmacophore modeling works. (4p)

10. Molecular docking algorithms have to be fast to screen large

libraries of drug candidates. Describe two approximations that make this
possible. (4p)

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Write  the  number  assigned  to  you  here:  

11. Briefly describe the fold recognition (threading) and homology (or
comparative) modeling methods. In what different situations do you use
these two methods? (5p)

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Write  the  number  assigned  to  you  here:  

12. The crystal structure of the Neurotensin receptor in complex with a

peptide was recently published. We are interested in studying the
properties of this peptide (13 amino acids long). First we extracted the
peptide conformation observed in the crystal structure and minimized
that structure in aqueous solution, which gave a total energy of -10
kcal/mol. After that, we ran a short molecular dynamics simulation of the
peptide in water for one nanosecond and minimized the final
conformation again. This time, the energy was different, -15 kcal/mol.

(A) Shouldn’t minimization give us the lowest energy? How is it possible

that we get different minimized energies?
(B) How is it possible that the peptide did not bind in its lowest energy
conformation?
(C) Re-docking of the peptide did not work. The RMSD between the
docked pose and the crystal conformation was 10 Å. Why do you think
the docking failed? (6p)

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13. Describe the terms of a typical molecular mechanics force field. You
should write down the equation, explain the variables, and explain with
words what they represent. (8p)

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Write  the  number  assigned  to  you  here:  

14. Describe all steps involved in setting up a molecular dynamics

simulation of a membrane protein with a ligand. You can assume that
there is a crystal structure of the protein with the ligand. The purpose of
the simulation is to analyze the dynamics of the protein. Try to be as
detailed as possible. (10p)

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 Table 4 | Binding affinities for 11 analogs of compound 3 against the dopamine D2 and D3 receptors
Table 4 | Binding affinities for 11 analogs of compound 3 against the dopamine D2 and D3 receptors
Receptor affinity (Ki, mM)b
Cmpd. Structure TCa D3 Receptor affinity (Ki, mM)D
b
2

Cmpd. Write  tStructure

he  
Cl
number  
O
assigned  
N
OH
to  you  here:   TCa D3 D2
Cl H2+ OH
53 O N
0.24 0.20 0.50
H2+
53 Cl
0.24 0.20 0.50
15. Recently,
Cl Cl
we found a new class of antagonists to the D3 dopamine
O
receptor.Cl
The Oligand N
was not very potent, Ki = 1.6μM. We now want to
54 0.29+
0.20
interesting 0.20
H O
optimize the affinity
O Nof this ligand and we have found several
2

54 H 0.292
+
0.20 0.20
analogsCl
of the lead compound in commercial chemical libraries (see
Cl Cl
one example below). Describe (in detail) the techniques you would use
© 2011 Nature America, Inc. All rights reserved.

O N
Cl +
55 H
to estimate the binding free energy0.28 0.20the two below 0.20
difference between
© 2011 Nature America, Inc. All rights reserved.

2
O N
H +
55 0.28 0.20
2 0.20
molecules Cl as accurately as possible? There is a crystal structure of the
OH
D3 dopamine Cl receptor, crystalized with a different antagonist. You will
Cl OH

56
have to Clcombine O several
N
methods0.25
and techniques described
0.08
in the 0.30
H +

56
course. (8p) O N 0.25
2

0.08 0.30
H2+
Cl

Cl Cl
O N
Cl
57 H2+ 0.24 A: Initial hit, K =0.30 2.60
O N
Compound i 1.6μM
57 H2+ 0.24 0.30 2.60
Cl

Cl Cl OH
O N
Cl
58 H2+ OH
0.27 0.30 0.80
O N
H2+
Compound B: One suggested
58 Cl
0.27 0.30 0.80
OH
analog to test.
Cl
Cl OH
O
59 Cl N
H 2+
0.24 0.30 1.20
O
59 N
H 2+
0.24 0.30 1.20
Cl

Cl Cl
O N
Cl
60 H2+ 0.24 0.10 0.60
OH
O N
60 H2+ 0.24 0.10 0.60
OH
Cl

Cl Cl
O N
Cl
61 H2+ 0.23 0.10 0.20
O N
61 H2+ 0.23 0.10 0.20
Cl

Cl Cl
O N
Cl
62 H2+ 0.26 0.10 0.60
O N
62 H2+ 0.26 0.10 0.60
Cl
OH
F Cl
F
OH
63 F F
F O 0.33 0.50 1.70
N
H2+
63 F
O 0.33 0.50 1.70
N
H2+
a
The Tanimoto similarity (Tc) to the most similar dopamine receptor ligand in the ChEMBL database. The uncertainty in each measured Ki is o 30%.
b

The Tanimoto similarity (Tc) to the most similar dopamine receptor ligand in the ChEMBL database. bThe uncertainty in each measured Ki is o 30%.
a

NATURE CHEMICAL BIOLOGY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemicalbiology 7

NATURE CHEMICAL BIOLOGY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemicalbiology 7

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