Complementarity and preorganization
Host
Guest
Supramolecule
(host-guest complex)
A supramolecular receptor (host) is a synthetic (abiotic) molecules that selectively (and reversibly) binds (recognizes) a selected substrate (guest).
Molecular recognition occurs through weak (non covalent, reversible…) interactions
HOW ?
Nature’s receptors
Neurotensin (see arrow) in the binding pocket of Neurotensin
Receptor 1 (NTSR1)
Which is the difference between the binding pocket and the remaining protein surface?
Nature’s vs manmade receptors
Avidin
K = 1013 M‐1 (H2O)
• Many interactions
• Tridimensional structure
K = 104 M‐1 (CDCl3)
Designing a receptor: the interactions
+
Guest:
3
Ka = 1.000.000 M‐1
Ionic pair interaction
+
‐
H
‐
Charge – dipol interaction
H‐bond
G = 34 KJ/mol
Interacting molecules are not receptors
3
3
3
3
Guest:
3
Receptors ?
• Weak binding
• No selectivity
Recognition at play
3
+
+
• Multiple interactions lead to selectivity
• Recognition involves desolvation, H‐G intraction are not the only one to consider
• Water is 55 M !!
• Entropy must be taken into account
From binding to recognition
Using a good interaction
H O
CH3
H
H O
H
H
O H O
Na
O H O
H
H
H O
2 “medium strenght” H‐bonds
CH3
H
H
O H O
Na
O H O
H
CF3
H
O
H O
H
H O
1 weaker H‐bond, 1 stronger H‐bond
From binding to recognition
If a single interaction is too weak, what about many?
H
H O
CH3
F
H
H
O H O
Na
O H O
H
H
H O
OH
H
H
O
HO
H
H O
O
F
H
H Na
O H O
F
H O
F
CH3
O
H
H O
H
O
H O
O
H O
H
H
H
H
G = G1 + G2 + …. H = H1 + H2 + …. Adding up interaction increases (in most cases) binding strength
S
From two species to three species (S < 0)
Difluoroethanol looses conformational entropy (S > 0) Summing up‐contributions
∆
∆
∆
∆
∆
∆
∆
Summing up‐contributions
∆
∆
∆
∆
∆
∆
∆
∆
M‐1
,
(M‐1)n
Generic association entropy
∏
∏
‐RTln[S] entropic correction applied to all the interactions but one
(non specific dilution entropy contribution, 10 KJ mol‐1 at 25 °C)
3 interactions, Kij = 1 M‐1  K = 3 × 103 M‐1 (water, 55.6 M)
Individual free energy contributions
One interaction removed
ΔΔ
Δ
ΔΔ
Δ
Intramolecular free energy contribution of each single interaction to the formation of the supramolecule. It can be positive!
Intermolecular free energy contribution for the association of the host and guest. It is mainly an entropic contribution but it may contain solvatation contributions.
Gas phase entropy of association
Entropic contributions to association:
• Translational entropy
• Rotational entropy
• Internal rotation entropy
• Vibrational entropy
Gas phase entropy of association
Translational entropy
Host (large) + Guest (small)
∆
∆
∝ ln
140 J mol‐1 K‐1 (MW 100 Da)
135
∆
40
Gas phase entropy of association
Rotational entropy
∆
100
∆
∝ ln
,
100 J mol‐1 K‐1 (MW 100 Da)
30
Gas phase entropy of association
Internal rotational and vibrational entropy
0
.
.
10
1
20
x bond
Low frequency (< 200 cm‐1) vibration
give a substantial contribution to entropy
Gas phase/solution entropy of association
∆
∆
135
∆
+∆
+∆
.
∆
Solvation Entropy
X = 140 J mol‐1 K‐1
140 + 0 ‐ 5 = ‐ 240 J mol‐1 K‐1
∆
.+
135
140 + 15 + x = ‐ 220 + x J mol‐1 K‐1
Association and solvation
H
H
H O
CH3
H O
F
H
H
O H O
Na
O H O
H
H
OH
H
H O
O
H
O
HO
F
H
H Na
O H O
F
H O
F
CH3
O
H
H O
H
O
H O
O
H O
H
H
H
H
G = GHG(gas) + GH(desolv) + Gg(desolv) + GHG (solv)
The solvation contribution reduces the entropic cost of association
The solvent‐solvent interaction may reduce the enthalpic cost of desolvation
Association and solvation
Δ
ΔΔ
Δ
C.A. Hunter, ANIE 2004, 43, 5310
Association and solvation
Δ
ΔΔ
Δ
C.A. Hunter, ANIE 2004, 43, 5310
Association and solvation
CHCl3
Δ
ΔΔ
Δ
C.A. Hunter, ANIE 2004, 43, 5310
Association and solvation
H2O
Δ
ΔΔ
Δ
C.A. Hunter, ANIE 2004, 43, 5310
Association and solvation
Δ
ΔΔ
Δ
C.A. Hunter, ANIE 2004, 43, 5310
Internal association entropy: preorganization
H
H
H O
CH3
H O
F
H
H
O H O
Na
O H O
H
H
OH
H
H O
O
H
O
HO
F
H
H Na
O H O
F
H O
F
CH3
O
H
H O
H
O
H O
O
H O
H
H
H
H
G = GHG(gas) + GH(desolv) + Gg(desolv) + GHG (solv)
The solvation contribution reduces the entropic cost of association
The solvent‐solvent interaction may reduce the enthalpic cost of desolvation
Freezing of internal rotation may imply significant additional entropic costs:
3 x 15 J mol‐1 K‐1 = 45 J mol‐1 K‐1  13 KJ mol‐1 (25°C)
1000‐fold reduction of K
Preorganization
Making the host more rigid is an advantage?
F
F
H
O HO
H
H
OH O
H
No entropy loss by the host in binding the guest.
Preorganization “the more highly hosts and guests are organized for binding and low solvation prior to their complexation, the more stable will be their complexes” (Cram)
What about the supramolecule?
Preorganization
Making the host more rigid is an advantage?
flexible
rigid
Expected reduction (3 rotors) = 1000‐fold
Low frequency vibrations compensate the entropy loss arising from rigidification
Preorganization
Making the host more rigid is an advantage?
G increase Expected = 3‐5 KJ mol‐1 per rotor
Found =  1.3 KJ mol‐1 per rotor
G increase Expected = 3‐5 KJ mol‐1 per rotor
Found =  0.4 KJ mol‐1 per rotor
Entropy‐enthalpy compensation
Increasing the interaction and host more rigidity is always an advantage?
3
3
Increase in binding sites makes the supramolecule more rigid.
Entropic contribution by low frequency vibration may compensate the entropic loss for reduced internal rotations
In some cases when binding becomes more enthalpically favorable, it becomes more entropically unfavorable. The net effect is that G remains fairly constant.
Complementarity
Why preorganization?
1) Selectivity
F
F
H
O HO
H
H
OH O
H
H O
CH3
H O
H
H
O H O
Na
O H O
H
H
O
H
H O
Na
Complementarity
Why preorganization?
2) Cost for higher energy conformation
H O
H Na
O H O
OH
HO
CH 3
HO
OH
O
H
H O
gauche‐like conformation
2.5 KJ mol‐1 for each
H O
Complementarity
Why preorganization?
3) Desolvatation
Few solvent molecules can accommodate a cavity
Less interacting solvent  high enthalpy
G = GHG(gas) + GH(desolv) + Gg(desolv) + GHG (solv)
Complementarity
Why preorganization?
4) Host self‐aggregation
Complementarity
“to complex, hosts must have binding sites which can simultaneously contact and attract the binding sites of the guests without generating internal strains or strong nonbonded
repulsions.” (Cram)
Complementarity
“to complex, hosts must have binding sites which can simultaneously contact and attract the binding sites of the guests without generating internal strains or strong nonbonded
repulsions.” (Cram)
R
R
N
N
N
N
N
N
N
NH 2
H 2N
N
H
O
R
O
N
N
H
O
Complementarity
G = 11.8 KJ/mol
G < 5 KJ/mol
Gass  0 KJ/mol
Δ
ΔΔ
Δ
GHB  3 KJ/mol
GMC  6 KJ/mol
Negative contribution of the missing interactions!!
The double mutant cycle
,
ΔΔ
Δ
Δ
,
,
Δ
,
Δ
,
,
Lock and key
“Lock and key”: at the beginnning of XX century Emil Fischer proposed this concept
to explain the extremely high selectivity of the interactions between proteins and their
substrates.
The idea was that the protein (receptor) contain a
poket with a shape complementary to that of the
substrate
The idea was brilliant but not completely correct:
the proteing changes its shape upon binding
assuming the one complementary to the substrate.
(induced fit)
Preorganization, complementarity, multiple interaction, shape fit  Selectivity
Hydrogen bonds in receptors
Strong
Weak
Hydrogen bonds in receptors
2 HB
G = ‐2.9 kCal mol‐1
3 HB
G = ‐3.0 kCal mol‐1
3 HB
G = ‐6  ‐7 kCal mol‐1
Hydrogen bonds in receptors
NH
N
NH
N
NH
N
Kass = 25 M-1
G = -1.9 kCal mol-1
Kass = 6.4×103 M-1
G = -5.2 kJ mol-1
Kass = 1.5×106 M-1
G = -8.4 kJ mol-1
Hydrogen bonds in receptors
‐
+
DA
+
‐
DAD
DAA
Hydrogen bonds in receptors
NH
N
Kass = 25 M-1
NH
N
NH
N
Kass = 6.4×103 M-1
Kass = 1.5×106 M-1
AA
Each H-bond contributes with 7.8 kJ mol-1
Each secondary interaction contributes with ± 2.9 kJ mol-1
AAA
Hydrogen bonds in receptors
Dipole‐ion interactions in receptors O
OH
O
OH
Cl
Cl
O
NaOH
OH
O
HO
O
O
O
O
O
O
O
Crown eters (Pedersen)
OH
Preorganization and Shape selectivity
Crown eters
Preorganization?
Crown eters: shape selectivity
• All crown ethers are selective for K+
• Size selectivity
• 18‐crown‐6 binds everything better