a multi state, allosterically regulated molecular receptor with...
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Journal Club 150521 Yi ZHOU
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A Multi-State, Allosterically-Regulated Molecular Receptor With Switchable Selectivity Mendez-Arroyo, J.; Barroso-Flores, J.; Lifschitz, A. M.; Sarjeant, A. A.; Stern, C. L.; Mirkin, C. A.*
J. Am. Chem. Soc. 2014, 136, 10340
1. Introduction
1.1 Allosteric Effect — Switchable Binding Activity to Substrate
Allosteric effect — The binding activity between an enzyme and its substrate could be regulated when
another small molecule (effector) binds to the regulation site.
Figure 1. Allosteric Regulation Process in Biological Enzymes
1.2 Two Types of Regulation Mechanism in Allosteric Enzymes (Figure 2.)
A. physical access to binding site (active/inactive)
B. chemical affinity of binding site (multiple active states)
1.3 Artificial Allosteric Systems
• Wide application in phase transfer catalysis, drug delivery,
sensing.
• Abiotic type-A regulation have been achieved with transition
metal coordination center regulation systems. (Figure 3.)
• However, switching between multiple active states
(type-B) remains challenging — modification of
chemical affinity without changing steric profile is
difficult.
1.4 This Work: Combination of Two Regulation
Types, Switchable Active States
! Design and synthesis of a Pt center regulated
receptor 1
! Regulation between inactive state 1 and two different active states 2 and 3 by anion effectors Cl- and
CN- by combination of two regulation mechanisms.
! Selective binding of two sterically similar guest molecules N-Methylpyridinium (5) and Pyridine N-
oxide (6) by two active states 3 and 2, respectively. (Figure 4.)
Binding Site
Regulation Site
AllostericEnzyme
Substrate
Effector
Switched Binding Activity
• No binding between enzyme and substrate before regulation
• Activated binding site by combining of effector on regulation site
• Substrate binds to the active state of enzyme
Figure 2. Two Regulation Types
Figure 3. Type-A Coordination Regulated System1
Type-A: steric access
Type-B: chemical affinity
Electrostatic force,Hydrogen bond,Dipole interaction, etc.
Effector
Effector
Rh
OPh2P
Ph2P O
spacer
spacer
Rh
O PPh2
PPh2O
guest
Rh
O
Ph2P
Ph2P
O
spacer
spacer
Rh
O
PPh2
PPh2
O
CO OCOC CO OC CO
CO
guest
Cl-Rh
O
Ph2P
Ph2P
O
spacer
spacer
Rh
O
PPh2
PPh2
O
Cl Cl
guest
OC CO
RhO
P P
O
CO, Cl-Rh
Cl
P CO
P
O
OClosed State Open State
Two states of Rh(I) center:
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2. Results and Discussion
2.1 System Design
Figure 4. Allosteric Regulation between inactive and Different Active States by Anion Effectors
2.1.1 Regulation Site — Stepwise Ligand Exchange on Pt(II) (Figure 5.)
• Step 1: Similar coordination strength between S-Pt
and Cl-Pt2 —dissociation of one sulfur ligand and
therefore formation of semi-open state 2
• Step 2: Strong coordination ability and trans effect
of CN- — substitution of both sulfur ligands and
cis/trans switch and therefore formation of fully open
state 3
2.1.2 Binding Site (Figure 4.)
• Calix[4]arene — Easily tuned conformation by modifications of upper and lower rims;
• Aromatic spacer — High affinity for small aromatic guests; Rigid backbone capable of transferring
modification from Pt center to calixarene.
2.1.3 Model Guest Molecules 5 and 6
• Aromatic ring capable of π-π stacking
• Similar size
• Different electrostatic property enabling selective binding
OO OO
S
HPh2P
S
HPh2P
Pt
Closed State 1(Inactivate)
2+
+ Cl-
- Cl-2CN-
OO OO
S S
Ph2P
Ph2P
PtCl
+
Semiopen State 2(Active for 6)
OO OO
S
Ph2P
S
Ph2PPt
CN
CN
Open State 3(Active for 5)
Regulation Site
Binding Site
Dissociation of one S Dissociation of both S
N NO
5 6
Figure 5. Three States of Pt(II)-Centered Coordination2
PtS
P P
S
Cl-Pt
S
P P
Cl
S
CORh
Cl
POC
P
S
SClosed State Semi-Open State Fully Open State
Step 1 Step 2
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2.2 NMR Titration — Selective Formation of Inclusion Complexes
Figure 6. NMR Trace of Guest 5 with Three States of Receptor
Upfield shift of ω-protons in 5 (Figure 6.) suggests the inclusion of the whole molecule into host cavity.
The shift is only observed with full open state 3, proving the selective binding of 5 by 3.
Similar phenomenon is observed between 2 and 6.
Figure 7. Comparison of NMR Signal Shift in Titration of 5 or 6 into Receptors 1-3
Comparison of the NMR signal shifts when titrating guest
molecules into different states of receptor (Figure 7.) indicates
the selective formation of 5⋂3 and 6⋂2.
2.3 Mechanism Interpretation — Crystal Strucure &
Computational
2.3.1 Inactive Closed State 1 (Physical inaccess)
Neither 5 nor 6 forms inclusion complex with receptor 1.
In solid state structure of 1 (Figure 8), the π−π interaction
between two aromatic spacers blocks the guest molecules from
entering the cavity.
5 with 1 (closed)No change in chemical shift
5 with 2 (semi-open)No change in chemical shift
5∩3 (fully open)Upfield shift of proton signal
Guest/Host Ratio
ω
α
βγ
N
Too small cavity
Figure 8. Solid-State Structure of State 1
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2.3.2 Active Semi-Open State 2 (Chemical affinity)
Only guest 6 is binded to receptor 2.
" Interactions in 6⋂2 (Figure 9.)
1) π−π stacking — π in 6 with π∗ in 2
2) Dipole-dipole — anti-parallel alignment of dipoles
3) n-σ* interaction — lone pair of O (6) with Pt(II) and
C–H σ∗ orbital (ethyl part of P,S ligand)
× 5 with 2
Both 5 and 2 are positively charged. The
electrostatic repulsion prevents the inclusion.
2.3.3 Active Fully Open State 3 (Chemical affinity)
Only cationic guest 5 is binded to receptor 3.
" Interactions in 5⋂3
π−π stacking — bonding orbital in 3 with
antibonding orbital in 5
× 6 with 3
According to the molecular orbitals involved in
π−π stackings of 6⋂2 and 5⋂3, the related MOs
in 6 and 3 are mismatched.
Switch between inactive and different active states by
combinatory regulation of physical accee (type-A) and chemical
affinity (type-B).
3. Conclusion
" Design and synthesis of a Pt(II) coordination regulated molecular receptor
" Switch between on/off states as well as multiple active states.
" Alteration of binding selectivity controlled by cavity size and electrostatic, dipole property, MO energy.
4. Referrence
i. Kawabara, J.; Stern, C. L.; Mirkin, C. A. J. Am. Chem. Soc., 2007, 129, 10074.
ii. (a) Anderson, G. K.; Kumar, R. Inorg. Chem. 1984, 23, 4064. (b) Kennedy, R. D.; Machan, C. W.;
McGuirk, C. M.; Rosen, M. S.; Stern, C. L.; Sarjeant, A. A.; Mirkin, C. A. Inorg. Chem. 2013, 52, 5876.
Figure 9. (a) Solid-State Structure of 6⋂2; (b) Side View of 6⋂2
(1) π-π stacking
(3) lone pair -σ*interaction
(2) dipole-dipoleinteraction
(a) (b)
(1) π-π stacking
(2) Not aligneddipoles
(a) (b)
Figure 10. (a) Solid-State Structure of 5⋂3; (b) Side View of 5⋂3