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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