Answers To Chapter 5: (In-Text & Asterisked Problems)

Introduction to Bioorganic Chemistry and Chemical Biology 1
Answers to Chapter 5
(in-text & asterisked problems)
Answer 5.1
PDB 3ZNF
C8
H27
C5
H21
Introduction to Bioorganic Chemistry and Chemical Biology | A5110

Van Vranken & Weiss | 978-0-8153-4214-4
Answer 5.2
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+H
2N NH2
NH
O O O
H H H
IRGERA N N N
N N N
H H H
O O O
NH O O-
+H NH2
+H 2N
2N NH2
NH
O O O
H H H
ent-IRGERA N N N
N N N
H H H
O O O
NH O O-
+H +H NH2
2N NH2 2N
NH
O O O
AREGRI H H H
N N N
N N N
H H H
O O O
NH O O-
+H
2N NH2
2 Introduction to Bioorganic Chemistry and Chemical Biology: Answers to Chapter 5
+H NH2
2N
NH
O O O
H H H
ent-AREGRI N N N
N N N
H H H
O O O
NH O O-
this “retro-inverso“ peptide is the best
+H
match of the natural sequence IRGERA 2N NH2
Answer 5.3
A For NKDVLRRMKK:
Residue Charge
Arg (R) +1 × 2
Lys (K) +1 × 3
+H N terminus +1 × 1
3
Glu (E) –1 × 0
Asp (D) –1 × 1
–O
2C– terminus –1 × 1
Net charge
+4
Similar calculations for RFRGDYFAK and KGNIDKFTEK yield net charges of +2 and
+1, respectively.
B The peptide is expected to bind better to a negatively charged surface through
ionic interactions, because opposite charges attract.
Answer 5.4
Residues in the peptide are labeled in red; residues in MDM2 are labeled in blue.
L26
V99
M62
W23 F19
L54
I61
I99
F91
L57
Answer
Van Vranken5.5
& Weiss | 978-0-8153-4214-4
H383, H387, and E411.
E411
H383
H387

Introduction to Bioorganic Chemistry and Chemical Biology: Answers to Chapter 5 3
Answer 5.6
+
O O O
H
-A: +
O: OH+ OH
H A HO HO HO

Van Vranken5.7
Answer & Weiss | 978-0-8153-4214-4
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HN
O N
O
O O
N
O N OH
H
Fmoc-PNA-T-OH
Van Vranken5.8
Answer & Weiss | 978-0-8153-4214-4
Pro and Gly prefer turns
Val, Ile, and Tyr prefer sheets
HO
O O
H
N N
N N
H H
NH OEt O O
O O Et O NH
H H
N N
N N
H O
O
OH
Answer 5.9
A A1,3 strain is most important for ϕ angles; A1,2 strain is most important for ψ angles.
B
O CONH O side chain
H
N side chain N CONH
H H H
= 0° = 160°
C Van Vranken & Weiss | 978-0-8153-4214-4
CONH O side chain
H
N side chain N CONH
H H H
= 0° = 160°
duction to Bioorganic Chemistry and Chemical Biology | A5117
Answer 5.10
ranken & Weiss | 978-0-8153-4214-4
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A H : OH
- O: OH
OH
+ S: + H A +S + A- S: S:
: .. R
HS
S S
H + R R
-A :
+ OH
2 +
S: S: R + S R S
S R S R
S S H
R R
.. -A:
R SH
Answer 5.11
Cys R R H :B
+
S S : PR 3 Cys-S P : OH2 Cys-S P O +
Cys R
R RR H
R R ..
-
Cys-S P O Cys-S P O - Cys-S: Cys-SH
:B H B
RR H RR
R
P O
R
R
Answer 5.12
There are seven WD domains in each half of the dimer, leading to a total of 14 WD
domains.
Answer 5.13
A H A H A
.. +H ..
HN 2N H2N H2N
R R R
R
.. N H : A- NH
NH2 R + R
R H
+H
3N
R R imine R
N: N N
R R + H : A- R
H
B -A:
enamine
R R H
R R R
NH
.. NH2+ ..NH2 NH2+ NH2
A H -A: H R R R
+H
2N H2N H2..N
A H
R R + H : A- R
NH
.. 2 N NH aldol cross-link
H
+H
R R R
3N
*Answer 5.14
NH3+ NH3+ NH3+ spinorphin: LVVYPWT OH
NH
O O O O
+H
H H
H2+ O O O O 3N N N N
H H H N N N O-
N N N N H H H
N N N O- O O O
H H H HO
O O O
NH
NH3+ H phakellistatin 13:
H2N NH2+ N cyclo-[FGPTLWP]
N
SV40 NLS sequence: PKKKRKV O
O O N O S
H S
N HN O N
O H N
OH H N HN
O NH2 H
N OO
H H O O NH
S H
O O O O O HO HN N
+H
H H H
3N N N N N
N N N N O- O O
H H H H
O O O O O
S
NH2 oxytocin: CYIQNCPLG malformin A: cyclo-[D C D CV D LI]
*Answer 5.15
A substance P RPKPQQFFGLM
B antimicrobial peptide cyclo-[RRWWRF]

or cyclo-[RWWRFR]
or cyclo-[WWRFRR]
or cyclo-[WRFRRW]
or cyclo-[RFRRWW]
or cyclo-[FRRWWR]
or cyclo-[RRWWRF]
C synthetic integrin antagonist CWLDVC
*Answer 5.17
A
Residue Charge
Arg (R) +1 × 0
Introduction
Lys (K)to Bioorganic Chemistry
+1 ×and
0 Chemical Biology | A5122
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+H N terminus design by www.blink.biz
3 +1 × 1
Glu (E) –1 × 0
Asp (D) –1 × 5
–O
2C terminus –1 × 1
Net charge –5
Residue Charge
Arg (R) +1 × 6
Lys (K) +1 × 2
+H
3N terminus +1 × 1
Glu (E) –1 × 0
Asp (D) –1 × 0
–O
2C terminus –1 × 0
Net charge +9
*Answer 5.19
H :B .. H B+
S S- -O S
O O
.. O
O O N
N N H
H H HN
HN HN
..
.. O
-O S O S
O O
N + H2N
H2
HN HN
B H ..
-S HS
O O
O O
H2N H2N
HN HN

*Answer 5.23
O O O
Asp Asp
O: H A OH+ R OH
A H
CF 3 +
NO : O
CF 3
CF 3 Asp
O O + O
O O
HO O:
H
: A-
*Answer 5.24
Trp Trp Trp

O O O -A:
H
+
O: OH+ OH
H A + N N N
Asp Asp Asp H H H
*Answer 5.26
A Initial protonation occurs on the amide carbonyl, not the amide nitrogen.
A Initial protonation occurs on the amide carbonyl, not the amide nitrogen.
.. H A
.. H A H : A-
O Ph Ph OH++ Ph OH OH O H : A- O
O Ph Ph OH Ph OH OH O O
Ph + +CPh3
R N Ph R N Ph R NH + +CPh3 R NH
.. H A R NH2++ R NH2
R N
H Ph R N
H Ph R NH R NH
.. H A R NH2 R NH2
H H Ph
H
H
Si i-Pr Ph + Ph
i-Pr Si i-Pr
i-Pr Ph + Ph
i-Pr H
.. i-Pr -
H Ph i-Pr i-Pr Ph
O .. -
O i-Pr - Si i-Pr Ph i-Pr Si i-Pr
i-Pr Ph
i-Pr
O O- i-Pr Si i-Pr Si i-Pr
CF 3COO i-Pr CF 3COO Ph Ph
CF 3 CF 3COO CF 3COO Ph H Ph
CF 3 H
B Protonation of N would disrupt the aromaticity of the imidazole ring.

B Protonation of N would disrupt the aromaticity of the imidazole ring.
Therefore initial protonation occurs on the N not N .
Therefore initial protonation occurs on the N not N .
Ph Ph Ph Ph Ph + Ph
Ph Ph Ph Ph H A Ph + Ph
Ph Ph .. H A H
Ph Ph H+ H
N N ..
N H
N+ - i-Pr Ph
N N N N i-Pr - Si i-Pr Ph
i-Pr Si i-Pr3SiO 2CCF 3 + Ph3C-H
i-Pr i-Pr3SiO 2CCF 3 + Ph3C-H
R N H A R N+ R N R N CF 3COO i-Pr
R ..
N H A R N
H+ R N
H R N
H CF 3COO
.. H H H
C +
C H A H +
H A H H
.. H
+O - i-Pr
R ..
O R +O R OH + i-Pr - Si i-Pr
R O R R OH + + i-Pr Si i-Pr3SiO 2CCF 3 + Ph3C-H
+ i-Pr i-Pr3SiO 2CCF 3 + Ph3C-H
CF 3COO i-Pr
CF 3COO
D
D .. H A
.. H A
O OH++ OH
O OH OH +
R R R + +
R N O R N O R N O +
N
H O N
H O N
H O
H H H
H: A-
A H OH O H: A- - O:: H A
A H OH O -O H A
R ..
.. R R R ....
+ CO2
+ CO2
R N O R N O R N O R NH2
N
H O N
H2++ O N
H2++ O NH2
H H2 H2
a concerted, one-step E2 mechanism is also plausible
a concerted, one-step E2 mechanism is also plausible
H +
H +
- i-Pr
-
i-Pr Si i-Pr
i-Pr Si i-Pr3SiO 2CCF 3 + Me3C-H
i-Pr i-Pr3SiO 2CCF 3 + Me3C-H
CF 3COO i-Pr
CF 3COO
E Note that protonation of thioethers is extremely unfavorable (pKa' < -8).

E Note that protonation of thioethers is extremely unfavorable (pKa' < -8).
H A H
.. H A
.. +H
Cys S Ph Cys +S Ph Cys SH + +CPh3
Cys S Ph Cys S Ph Cys SH + +CPh3
Ph Ph Ph
Ph Ph
Ph Ph Ph
H Ph + Ph
H Ph + Ph
- i-Pr
i-Pr - Si i-Pr Ph
i-Pr Si i-Pr3SiO 2CCF 3 + Ph3C-H
i-Pr Ph i-Pr3SiO 2CCF 3 + Ph3C-H
CF 3COO i-Pr
CF 3COO
Introduction
Van Vranken &to Bioorganic
Weiss Chemistry and Chemical Biology | A5132
| 978-0-8153-4214-4
*Answer 5.28
A KVKVKVKVKVKVK, because β-branched amino acids have high β-sheet propensities
and low α-helix and turn propensities.
B GPPGPPGPPGPPGPPGPPGPP, because Pro has low α-helix and β-sheet propensities.
C NLEDKAEELLSKNYHLENEVARL, because it has a leucine zipper motif with Leu at
every seven residues.
D GPPGPPGPPGPPGPPGPPGPP, because (GPP)n forms a collagen triple helix.
E GPPGPPGPPGPPGPPGPPGPP, because Pro has low α-helix and β-sheet propensities.
*Answer 5.31
A The calcium-binding loops are underlined: MADQLTEEQIAEFKEAFSLFDKDG-
DGTITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTMMARKMK-
DTDSEEEIREAFRVFDKDGNGYISAAELRHVMTNLGEKLTDEEVDEMIREADIDG-
DGQVNYEEFVQMMTAK
B The first calcium-binding loop is positions 21–32, -DKDGDGTITTKE-. The first and
last positions of the calcium-binding loop are the only positions conserved as ani-
onic amino acids. Therefore Asp21 and Glu32 are most likely to bind as anionic car-
boxylates. In the crystal structure for PDB 1CFC, both of the side-chain carboxylate
oxygens of Glu32 bind to the calcium ion. Because asparagines are also tolerated
at the second and third ligand positions, Asp23 and Asp25 probably coordinate as
neutral ligands through the side-chain carbonyls. Because phenylalanine is also tol-
erated at the fourth ligand position, it is likely that the backbone carbonyl, and not
the side chain, is coordinating to calcium. Because serine is a common ligand for the
fifth position, Thr29 probably binds through the side-chain hydroxyl. As a result of
the high pKa of alcohols compared with carboxylic acids, Thr29 probably binds as a
neutral OH ligand.
Asp25
H
N O Thr27
HN
Asp23 OH OH
O
O O NH
HN OH
O Ca OH NH
Thr29
O O
CH3 O
O O
Asp21 O
HN
NH
Glu32
O
C Van
Glycine
Vrankenis& Weiss
highly flexible and can adopt tight turns. Isoleucine and valine are
| 978-0-8153-4214-4
β-branched hydrophobic amino acids that limit the flexibility of the side chain and
loop.
*Answer 5.32
A Two types of dimers are known. The dimer based on swapping the S-peptide (PDB
1BSR) has the S-peptide from the first molecule bound in the cleft of the second
molecule, and vice versa.
domain-swapped dimer
B There may be many solutions to this problem. Any mutation to the loop that prevents
the helix from binding to the cleft in residues 1–113 will favor the formation of the
domain-swapped dimer. Investigators have induced dimerization by generating a
deletion variant Δ(114:119) that lacks the flexible loop.
wild type protein deletion

engineering mutant
(truncate loop)

*Answer 5.36
A 1,3 strain bonds with limited rotation due to A1,3 strain
R R'
H HO
R"
O O OH O O
R H OH NH2
R"
R' OH
*Answer 5.38
A Cys28 makes contacts with DNA (rendered as a brown surface).
B The nearby cysteine residue is Cys120.

C CysteineS thiols
H
are Hefficient at conjugate addition reactions.
Cys O
S H H O
Cys
H O
O HO
SO
H Cys
HO
O to Bioorganic Chemistry and Chemical Biology | A5143
Introduction S
Cys
*Answer 5.41
resonance-stabilized
R R R
X• H X H + • etc
O
•O
O
O R O R tautomerization OH R
H
• •
H
R O R O R HO
keto tautomers enol tautomers (aromatic)

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Answers To Chapter 5: (In-Text & Asterisked Problems)

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Introduction to Bioorganic Chemistry and Chemical Biology 1

Introduction to Bioorganic Chemistry and Chemical Biology | A5110

Introduction to Bioorganic Chemistry and Chemical Biology | A5113

Introduction to Bioorganic Chemistry and Chemical Biology | A5114

B antimicrobial peptide cyclo-[RRWWRF]

C synthetic integrin antagonist CWLDVC

Introduction to Bioorganic Chemistry and Chemical Biology | A5125

Trp Trp Trp

B Protonation of N would disrupt the aromaticity of the imidazole ring.

E Note that protonation of thioethers is extremely unfavorable (pKa' < -8).

wild type protein deletion

Introduction to Bioorganic Chemistry and Chemical Biology | A5136

A 1,3 strain bonds with limited rotation due to A1,3 strain

B The nearby cysteine residue is Cys120.

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