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Introduction to Bioorganic Chemistry and Chemical Biology 1
Answers to Chapter 5(in-text & asterisked problems)
Answer 5.1
Answer 5.2Introduction to Bioorganic Chemistry and Chemical Biology | A5110Van Vranken & Weiss | 978-0-8153-4214-4 © www.garlandscience.com design by www.blink.biz
PDB 3ZNF
H27
H21
C8
C5
Introduction to Bioorganic Chemistry and Chemical Biology | A5111Van Vranken & Weiss | 978-0-8153-4214-4 © www.garlandscience.com design by www.blink.biz
NH
HN
NH
HN
NH
HN
O
O
O
O
O
O
NH
NH2+H2N
O -
NH
NH2+H2N
O
NH
HN
NH
HN
NH
HN
NH
NH2+H2N
O -
NH
NH2+H2N
O
O
O
O
O
O
O
NH
HN
NH
HN
NH
HN
O
O
O
O
O
O
NH
NH2+H2N
O -
NH
NH2+H2N
O
IRGERA
AREGRI
ent-IRGERA
2 Introduction to Bioorganic Chemistry and Chemical Biology: Answers to ChApter 5
Answer 5.3
A For nKDVLrrMKK:
Residue Charge
Arg (r) +1 × 2
Lys (K) +1 × 3
+h3n terminus +1 × 1
Glu (e) –1 × 0
Asp (D) –1 × 1
–o2C– 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.
Answer 5.5
h383, h387, and e411.
Introduction to Bioorganic Chemistry and Chemical Biology | A5111Van Vranken & Weiss | 978-0-8153-4214-4 © www.garlandscience.com design by www.blink.biz
NH
HN
NH
HN
NH
HN
NH
NH2+H2N
O -
NH
NH2+H2N
O
O
O
O
O
O
O
ent-AREGRI
this “retro-inverso“ peptide is the best match of the natural sequence IRGERA
Introduction to Bioorganic Chemistry and Chemical Biology | A5112Van Vranken & Weiss | 978-0-8153-4214-4 © www.garlandscience.com design by www.blink.biz
L26
W23 F19L54
I99
L57
V99
F91
I61
M62
Introduction to Bioorganic Chemistry and Chemical Biology | A5113Van Vranken & Weiss | 978-0-8153-4214-4 © www.garlandscience.com design by www.blink.biz
H383
H387
E411
Introduction to Bioorganic Chemistry and Chemical Biology: Answers to ChApter 5 3
Answer 5.6
Answer 5.7
Answer 5.8
Answer 5.9
A A1,3 strain is most important for ϕ angles; A1,2 strain is most important for ψ angles.
B
C
Answer 5.10
Introduction to Bioorganic Chemistry and Chemical Biology | A5114Van Vranken & Weiss | 978-0-8153-4214-4 © www.garlandscience.com design by www.blink.biz
O
OH A
O
OH+
O
OH
+
H+-A
HO HO HO: :
Introduction to Bioorganic Chemistry and Chemical Biology | A5115Van Vranken & Weiss | 978-0-8153-4214-4 © www.garlandscience.com design by www.blink.biz
NH
NO
O
OH
OO
N
HN
O
O
Fmoc-PNA-T-OH
Introduction to Bioorganic Chemistry and Chemical Biology | A5116Van Vranken & Weiss | 978-0-8153-4214-4 © www.garlandscience.com design by www.blink.biz
O
N
NHNH
O
O
HN
HN
O O
N
NHHN
O
O
NH
NH
O
O
OEt
Et
HO
OH
Pro and Gly prefer turnsVal, Ile, and Tyr prefer sheets
Introduction to Bioorganic Chemistry and Chemical Biology | A5117Van Vranken & Weiss | 978-0-8153-4214-4 © www.garlandscience.com design by www.blink.biz
NH
O
CONHNH
O
H
= 0°
CONH
= 160°
H
side chain
side chain
Introduction to Bioorganic Chemistry and Chemical Biology | A5117Van Vranken & Weiss | 978-0-8153-4214-4 © www.garlandscience.com design by www.blink.biz
NH
O
CONHNH
O
H
= 0°
CONH
= 160°
H
side chain
side chain
Introduction to Bioorganic Chemistry and Chemical Biology | A5118Van Vranken & Weiss | 978-0-8153-4214-4 © www.garlandscience.com design by www.blink.biz
- OS
OHS+
HS R..
HA
++ A-OHSS
H R
: :
+-A
:
:
OHSS
R
:
:
+:
OH2
SS
R
:
H A
+
SS
R
:+
SHR..
SRS
R
H
+
-A:
SRS
R
4 Introduction to Bioorganic Chemistry and Chemical Biology: Answers to ChApter 5
Answer 5.11
Answer 5.12
there are seven wD domains in each half of the dimer, leading to a total of 14 wD domains.
Introduction to Bioorganic Chemistry and Chemical Biology | A5119Van Vranken & Weiss | 978-0-8153-4214-4 © www.garlandscience.com design by www.blink.biz
PR3:SSCys
CysP
RCys-S
RR
+OH2: P
RCys-S
RRO
H
PR
OR
R
Cys-S:-
H+
PR
Cys-S
RRO
H B:
B:
PR
Cys-S
RRO -..
H B Cys-SH
Introduction to Bioorganic Chemistry and Chemical Biology | A5120Van Vranken & Weiss | 978-0-8153-4214-4 © www.garlandscience.com design by www.blink.biz
NHR
HA +H2NR
NH2+
R
-A H
NH2R
enamine
..:
.. NH2+
R
H2NR
H
..HA
-A:
NH2R
H2NR
aldol cross-linkNH
R
R
H+ A-:NH
R
R
HNR
..H A
+H2NR
NH2R
..
H2N RN
RH
H+
H2N RNH
R
.. H A
A-:
+H3N RN
RH
:R
NR H+ A-:
RN
R
imine
NH2R
+H3NR
..
A
B
Introduction to Bioorganic Chemistry and Chemical Biology | A5121Van Vranken & Weiss | 978-0-8153-4214-4 © www.garlandscience.com design by www.blink.biz
NH
HN
NH
HN
NH
NNH
+H3NO
O
O
O
O
O
OHN
OO -
O
S
NH2O
NH2
O
S
OHHN O
OO
N
NH
O
O
HN
HN
HO
NH
O
N
O
NH
H
H2+
NNH
HN
NH
HN
NH
O
O
O
O
O
NH
O
HN
NH3+
O -
O
NH3+
NH3+
H2N NH2+
NH3+
+H3NNH
HN
NH
NNH
HN
O -
O
O
O
O
O
O
O
HO
OHNH
HN
OO O
N
HNNH
O
HN
O
SS
H
spinorphin: LVVYPWT
SV40 NLS sequence: PKKKRKV
cyclo-[FGPTLWP]
oxytocin: CYIQNCPLG malformin A: cyclo-[DC DCV DLI]
phakellistatin 13:
Answer 5.13
*Answer 5.14
Introduction to Bioorganic Chemistry and Chemical Biology: Answers to ChApter 5 5
*Answer 5.15
*Answer 5.17
A
Residue Charge
Arg (r) +1 × 0
Lys (K) +1 × 0
+h3n terminus +1 × 1
Glu (e) –1 × 0
Asp (D) –1 × 5
–o2C terminus –1 × 1
net charge –5
B
Residue Charge
Arg (r) +1 × 6
Lys (K) +1 × 2
+h3n terminus +1 × 1
Glu (e) –1 × 0
Asp (D) –1 × 0
–o2C terminus –1 × 0
net charge +9
Introduction to Bioorganic Chemistry and Chemical Biology | A5122Van Vranken & Weiss | 978-0-8153-4214-4 © www.garlandscience.com design by www.blink.biz
cyclo-[RRWWRF]
RPKPQQFFGLM
CWLDVC
or cyclo-[RWWRFR]or cyclo-[WWRFRR]or cyclo-[WRFRRW] or cyclo-[RFRRWW] or cyclo-[FRRWWR] or cyclo-[RRWWRF]
A substance P
B antimicrobial peptide
C synthetic integrin antagonist
6 Introduction to Bioorganic Chemistry and Chemical Biology: Answers to ChApter 5
*Answer 5.19
*Answer 5.23
*Answer 5.24
Introduction to Bioorganic Chemistry and Chemical Biology | A5125Van Vranken & Weiss | 978-0-8153-4214-4 © www.garlandscience.com design by www.blink.biz
NH
OO
S
NH
OS -..
NH
- O
H B
S
NH2
+
- O S
H B+
..
:
..
HN
O
HN
O
HN
O
HNH2N
O
HN
SO..
OO
H2NO
HN
- S
O
HB ..
H2NO
HN
HS
Introduction to Bioorganic Chemistry and Chemical Biology | A5129Van Vranken & Weiss | 978-0-8153-4214-4 © www.garlandscience.com design by www.blink.biz
H A
O
OH+
O
OHR
+
O+
OH
CF3
A-
OHO
CF3
O
OAsp
:
:
:
Asp
O O
CF3 O
OAsp
:
HA
NO
Introduction to Bioorganic Chemistry and Chemical Biology | A5130Van Vranken & Weiss | 978-0-8153-4214-4 © www.garlandscience.com design by www.blink.biz
O
OAsp H A
O
OH+
Asp
O
OHAsp
+ NH
NH
H +-A
NH
:
:
Trp Trp Trp
Introduction to Bioorganic Chemistry and Chemical Biology: Answers to ChApter 5 7
*Answer 5.26
Introduction to Bioorganic Chemistry and Chemical Biology | A5132Van Vranken & Weiss | 978-0-8153-4214-4 © www.garlandscience.com design by www.blink.biz
Ph Ph
R NH
O
Ph H A..
PhPh
R NH
OH+
Ph
OH
NHR+ +CPh3
OH
NHR
O
NH2+R
H A-:
R NH2
O
Ph
Ph
PhHCF3COO
Sii-Pr i-Pr
i-Pr
Ph Ph
PhH
Sii-Pri-Pri-Pr
CF3COO
HSi
i-Pr i-Pri-Pr
O -O
CF3
+
-..
H A..
H APh
R N
NPh
Ph
H A..
Ph
R NH+
NPh
Ph
R NH
N..
Ph Ph
PhH
Sii-Pri-Pri-Pr
CF3COO
+
-i-Pr3SiO2CCF3 + Ph3C-H
R NH
HN+
R O..
H A+
+R OH
H
Sii-Pri-Pri-Pr
CF3COO
+
-i-Pr3SiO2CCF3 + Ph3C-H
R OH
+
NH
O
OH+ OH
ONH
+
H A..
RNH
O
O
R R
H
Sii-Pri-Pri-Pr
CF3COO
+-
i-Pr3SiO2CCF3 + Me3C-H
OH
ONH
R ..HA O
ONH2
+
R
H A-: - O
ONH2
+
R
:
NH2R + CO2..
H A
a concerted, one-step E2 mechanism is also plausible
+
..
Ph Ph
Cys S Ph
H A
Ph Ph
Cys S PhH
++ +CPh3
Cys SH
Ph Ph
Ph
H
Sii-Pri-Pri-Pr
CF3COO
+-
i-Pr3SiO2CCF3 + Ph3C-H
Ka' < -8).
A Initial protonation occurs on the amide carbonyl, not the amide nitrogen.
C
D
E
B Protonation of N would disrupt the aromaticity of the imidazole ring. Therefore initial protonation occurs on the N not N .
Note that protonation of thioethers is extremely unfavorable (p
Introduction to Bioorganic Chemistry and Chemical Biology | A5132Van Vranken & Weiss | 978-0-8153-4214-4 © www.garlandscience.com design by www.blink.biz
Ph Ph
R NH
O
Ph H A..
PhPh
R NH
OH+
Ph
OH
NHR+ +CPh3
OH
NHR
O
NH2+R
H A-:
R NH2
O
Ph
Ph
PhHCF3COO
Sii-Pr i-Pr
i-Pr
Ph Ph
PhH
Sii-Pri-Pri-Pr
CF3COO
HSi
i-Pr i-Pri-Pr
O -O
CF3
+
-..
H A..
H APh
R N
NPh
Ph
H A..
Ph
R NH+
NPh
Ph
R NH
N..
Ph Ph
PhH
Sii-Pri-Pri-Pr
CF3COO
+
-i-Pr3SiO2CCF3 + Ph3C-H
R NH
HN+
R O..
H A+
+R OH
H
Sii-Pri-Pri-Pr
CF3COO
+
-i-Pr3SiO2CCF3 + Ph3C-H
R OH
+
NH
O
OH+ OH
ONH
+
H A..
RNH
O
O
R R
H
Sii-Pri-Pri-Pr
CF3COO
+-
i-Pr3SiO2CCF3 + Me3C-H
OH
ONH
R ..HA O
ONH2
+
R
H A-: - O
ONH2
+
R
:
NH2R + CO2..
H A
a concerted, one-step E2 mechanism is also plausible
+
..
Ph Ph
Cys S Ph
H A
Ph Ph
Cys S PhH
++ +CPh3
Cys SH
Ph Ph
Ph
H
Sii-Pri-Pri-Pr
CF3COO
+-
i-Pr3SiO2CCF3 + Ph3C-H
Ka' < -8).
A Initial protonation occurs on the amide carbonyl, not the amide nitrogen.
C
D
E
B Protonation of N would disrupt the aromaticity of the imidazole ring. Therefore initial protonation occurs on the N not N .
Note that protonation of thioethers is extremely unfavorable (p
8 Introduction to Bioorganic Chemistry and Chemical Biology: Answers to ChApter 5
*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.
C Glycine is highly flexible and can adopt tight turns. Isoleucine and valine are 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.
Introduction to Bioorganic Chemistry and Chemical Biology | A5135Van Vranken & Weiss | 978-0-8153-4214-4 © www.garlandscience.com design by www.blink.biz
Ca
OO
O
O
OH
OO
OH
OH
NH
CH3
O
HNOH
HN
HN
HN
O
O
O
NH
O
NH
O
Asp21
Glu32
Asp23
Asp25
Thr27
Thr29
Introduction to Bioorganic Chemistry and Chemical Biology | A5136Van Vranken & Weiss | 978-0-8153-4214-4 © www.garlandscience.com design by www.blink.biz
domain-swapped dimer
domain-swapped dimer
proteinengineering
(truncate loop)
wild type deletionmutant
Introduction to Bioorganic Chemistry and Chemical Biology: Answers to ChApter 5 9
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.
*Answer 5.36
*Answer 5.38
A Cys28 makes contacts with DnA (rendered as a brown surface).
B the nearby cysteine residue is Cys120.
C Cysteine thiols are efficient at conjugate addition reactions.
Introduction to Bioorganic Chemistry and Chemical Biology | A5136Van Vranken & Weiss | 978-0-8153-4214-4 © www.garlandscience.com design by www.blink.biz
domain-swapped dimer
domain-swapped dimer
proteinengineering
(truncate loop)
wild type deletionmutant
Introduction to Bioorganic Chemistry and Chemical Biology | A5141Van Vranken & Weiss | 978-0-8153-4214-4 © www.garlandscience.com design by www.blink.biz
O
NH2
OOH
OH
HO
OO
OH
R
R'R"
H
R
R"H
R'
bonds with limited rotation due to A1,3 strain A1,3 strain
Introduction to Bioorganic Chemistry and Chemical Biology | A5143Van Vranken & Weiss | 978-0-8153-4214-4 © www.garlandscience.com design by www.blink.biz
O
O
O
H
H
H
HO
S
S
Cys
Cys
Introduction to Bioorganic Chemistry and Chemical Biology | A5143Van Vranken & Weiss | 978-0-8153-4214-4 © www.garlandscience.com design by www.blink.biz
O
O
O
H
H
H
HO
S
S
Cys
Cys
10 Introduction to Bioorganic Chemistry and Chemical Biology: Answers to ChApter 5
*Answer 5.41
Introduction to Bioorganic Chemistry and Chemical Biology | A5145Van Vranken & Weiss | 978-0-8153-4214-4 © www.garlandscience.com design by www.blink.biz
X• OH X H
•O
+
R
O
R
•
O
R
•
O
R
•
O
OR
R OH
HOR
RH
H
R
etc
tautomerization
resonance-stabilized
keto tautomers enol tautomers (aromatic)