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Chaotropes & Kosmotropes and theDriving Force of the Salting Effect
Ronen Zangi
Department of Organic Chemistry I
University of the Basque Country, UPV/EHU
San Sebastian, Spain
The 14th ISSP, 25–30 July 2010
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The Salting Problem and its Significance
How does the solvent induced interaction between solute particles varywhen salts of different types are dissolved in the aqueous solution?
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The Salting Problem and its Significance
How does the solvent induced interaction between solute particles varywhen salts of different types are dissolved in the aqueous solution?
www.u.arizona.edu/weichsel
• Protein solubility:
crystallization and aggregation
Nature
Rev.DrugDisc.
3,301(2004)
• Recognition between proteins and multimerization
• Catalytic activity of enzymes
• Stability of secondary and tertiary structures
www.isis.rl.ac.uk
• Phase boundaries of micellar solutions and lipid bilayers
• Cloud point of non-ionic surfactants
• Polymer swelling
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Characteristics of the Salting Phenomenon
• It becomes important at moderate salt concentrations: 0.01–1.0 M
• Additive over all ions in solution; anions have larger effect than cations
• The dependence of solute solubility on salt concentration:
log(S0/S) = KsCs Salting-Out: Ks > 0 Salting-In: Ks < 0stronger solute-solute interactions weaker solute-solute interactions
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Characteristics of the Salting Phenomenon
• It becomes important at moderate salt concentrations: 0.01–1.0 M
• Additive over all ions in solution; anions have larger effect than cations
• The dependence of solute solubility on salt concentration:
log(S0/S) = KsCs Salting-Out: Ks > 0 Salting-In: Ks < 0stronger solute-solute interactions weaker solute-solute interactions
0.0 0.2 0.4 0.6 0.8 1.0 1.2Cs [equivalents/L]
-0.2
-0.1
0.0
0.1
0.2
log(
S0 /
S)
1/2 Na2SO4NaF, NaOH
NaClKClNaBrLiCl, RbClKBr, NaNO3NaClO4, NH4ClCsCl
HCl
CsI, KO2C7H5
HClO4
(CH3)4NBr
benzeneLong & McDevit, Chem. Rev. 51, 119 (1952)
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Characteristics of the Salting Phenomenon
• It becomes important at moderate salt concentrations: 0.01–1.0 M
• Additive over all ions in solution; anions have larger effect than cations
• The dependence of solute solubility on salt concentration:
log(S0/S) = KsCs Salting-Out: Ks > 0 Salting-In: Ks < 0stronger solute-solute interactions weaker solute-solute interactions
0.0 0.2 0.4 0.6 0.8 1.0 1.2Cs [equivalents/L]
-0.2
-0.1
0.0
0.1
0.2
log(
S0 /
S)
1/2 Na2SO4NaF, NaOH
NaClKClNaBrLiCl, RbClKBr, NaNO3NaClO4, NH4ClCsCl
HCl
CsI, KO2C7H5
HClO4
(CH3)4NBr
benzeneLong & McDevit, Chem. Rev. 51, 119 (1952)
0.0 0.2 0.4 0.6Cs [equivalents/L]
-0.2
-0.1
0.0
log(
S0 /
S)
1/2 Na2SO4
NaCl
KOOCH
KCl, NaNO3
1/2 MgCl2
KNO3
Co(NO3)3(NH3)3
NaOOCH
• Salting-In enhances for larger and more polar solutes
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Hofmeister Series
The ranking of the (Salting-Out and Salting-In) ions to precipitate proteins:
PO3−4 > SO2−
4 > HPO2−4 > OH− > F− > Cl− > Br− > NO−3 > I− > SCN− > ClO−4
Al3+ > Mg2+ > Ca2+ > Ba2+ > Na+ > K+ > NH+4 > Rb+ > Cs+
stronger solute-solute interactions weaker solute-solute interactions=⇒⇐= ‖
=⇒ Attraction between the proteins increases with ionic charge density
+
−
w ε> Hεw
ww
ww
w
H
H
Proposed Explanations
↗
↘
Electrostatic theories
problems with predicting salting-in behavior
Changes in the structure of water
? Kosmotropic ions - order the structure of water =⇒ Salting-Out
? Chaotropic ions - disorder the structure of water =⇒ Salting-In
problems with accounting for different behavior of the same salt
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Molecular Dynamics Simulations
Two Hydrophobic Plates (∅ ∼ 2.1 nm)solvated in aqueous electrolyte solutions
σplt = 0.40 nmεplt = 0.50 kJ/mol
SPC/E water
+0.4238+0.4238
−0.8476
N = 1090 molecules
Salt : 30 anions & 30 cations
+0.5e
+1.0e
+1.5e−1.5e
−1.0e
−0.5e
1.43 molal(1.20–1.35 M)
σion = 0.50 nmεion = 1.00 kJ/mol
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Molecular Dynamics Simulations
Two Hydrophobic Plates (∅ ∼ 2.1 nm)solvated in aqueous electrolyte solutions
σplt = 0.40 nmεplt = 0.50 kJ/mol
SPC/E water
+0.4238+0.4238
−0.8476
N = 1090 molecules
Salt : 30 anions & 30 cations
+0.5e
+1.0e
+1.5e−1.5e
−1.0e
−0.5e
1.43 molal(1.20–1.35 M)
σion = 0.50 nmεion = 1.00 kJ/mol
Potential of Mean Force
z
fixed fixed21
12
⟨r̂
12· (~F1 − ~F2)
⟩~r1,~r2
= −∂w(r12
)/∂r12⟨
r̂⊥ · (~F1 − ~F2)⟩~r1,~r2
= 0
T=300 K
P=1 atm
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Changes in the Hydrophobic Interaction asa Function of the Type of Salt in Solution
Free energy profile of bringing
the plates from far apart to contact
Free energy difference for association
process: P(aq) + P(aq) P2(aq)
0.40 0.50 0.60 0.70 0.80 0.90 1.00 1.10 1.20 1.30 1.40d [nm]
-200
-180
-160
-140
-120
-100
-80
-60
-40
-20
0
w(r
) [k
J/m
ol]
q = 0.50q = 0.60q = 0.70no ionsq = 1.00q = 1.20q = 1.40
0.50 0.60 0.70 0.80 0.90 1.00 1.10 1.20 1.30 1.40q [e]
-200.0
-190.0
-180.0
-170.0
-160.0
-150.0
-140.0
∆G(q
) [k
J/m
ol]
no ions
salting-outsalting-in
R. Zangi, M. Hagen & B. J. Berne, J. Am. Chem. Soc. 129, 4678 (2007)
Salting-In ions: q < 0.90 eweaker effective interaction between plates
Salting-Out ions: q > 0.90 estronger effective interaction between plates
• Why did the effective interaction change?
• Can the variation be predicted?
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The Corresponding Changes in Water Structure
0.25 0.30 0.35 0.40 0.45 0.50 0.55r [nm]
0.8
1.2
1.6
2.0
2.4
2.8
3.2
3.6
gO
-O(r
)
q=0.50 e
q=0.90 e
q=1.40 e
no-ions
Water-Water RDF
0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4q [e]
3.0
3.1
3.2
3.3
3.4
3.5
3.6
gO
-O(r
=0.2
74 n
m)
salting-outsalting-in
no-ions
0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4
q [e]
3.0
3.1
3.2
3.3
3.4
3.5
# o
f H
ydro
gen B
onds
salting-outsalting-in
Interactions Between Water Molecules
no-ions
0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4
q [e]
-20.0
-19.0
-18.0
-17.0
-16.0
-15.0
Energ
y [k
J/m
ol]
no-ions
salting-outsalting-in
Potential Energy
no-ions Hydrogen Bond Energy
R. Zangi, J. Phys. Chem B. 114, 643 (2010)
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The Corresponding Changes in Water Dynamics
Salting-out ions induce an increase in the viscosity,and a decrease in the rotational decay rate of water.Vise versa for salting-in ions.
0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4
q [e]
0.60
0.65
0.70
0.75
0.80
η [
10
-3 k
g m
-1 s
-1]
salting-outsalting-in
Viscosity of Water
no-ions
0.30
0.32
0.34
0.36
0.38
kro
t [ps
-1] (N
orm
al to
the M
ol. P
lane)
salting-in salting-out
Rotational Decay Rate
no-ions
0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4
q [e]
0.18
0.19
0.20
0.21
0.22
0.23
0.24
kro
t [ps
-1] (D
ipole
Mom
ent)
no-ionssalting-in salting-out
It is the strength of the ion-water interactions,and not the ion-induced structural changes of water, that affect the dynamics of water.
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A Thermodynamic View: Preferential Binding
Linked Functions: J. Wyman, Adv. Protein Chem. 19, 224 (1964)
C. Tanford, J. Mol. Biol. 39, 539 (1969)
Consider the reaction: A(aq) + B(aq) C(aq)
Now, add a ligand (salt) X that can (in addition to water) interact with A, B and C
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A Thermodynamic View: Preferential Binding
Linked Functions: J. Wyman, Adv. Protein Chem. 19, 224 (1964)
C. Tanford, J. Mol. Biol. 39, 539 (1969)
Consider the reaction: A(aq) + B(aq) C(aq)
Now, add a ligand (salt) X that can (in addition to water) interact with A, B and C
A + iX + jW AXiWj i = 0, 1, . . . , p ; j = p− i
B + kX + lW BXkWl k = 0, 1, . . . , q ; l = q− k
C + mX + nW CXmWn m = 0, 1, . . . , r ; n = r−m
How does the addition of X affect the equilibrium constant of the reaction?
In the limit of infinite dilution of A, B and C =⇒
d lnK
d ln aX
= νX,C− ν
X,A− ν
X,B−
nX
nW
(νW,C− ν
W,A− ν
W,B) ≡ ∆ν
X, pref
νY,M
= number of Y molecules bound to M macromolecule
aX
= chemical activity of X
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Binding/Exclusion of the Ions and Water
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Relation between ∆νpref and ∆G
∆νions, pref = (∆νcations + ∆νanions)/2−nsalt
nwater
∆νwater
0.50 0.60 0.70 0.80 0.90 1.00 1.10 1.20 1.30 1.40q [e]
-7.0
-6.0
-5.0
-4.0
-3.0
-2.0
-1.0
0.0
1.0
2.0
3.0
∆νio
ns, p
ref (q
)
salting-outsalting-in
binding
exclusion
P(aq) + P(aq) P2(aq)
binding of the ions =⇒ salting-inexclusion of the ions =⇒ salting-out
d(∆G) = −RT∆νions, pref · d ln aions
-6.0 -5.0 -4.0 -3.0 -2.0 -1.0 0.0 1.0 2.0∆νions, pref (q)
-200.0
-190.0
-180.0
-170.0
-160.0
-150.0
-140.0
-130.0
∆G(q
) [k
J/m
ol]
salting-out
salting-in
exclusionbinding
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Mechanism of Salting-In and Salting-Out
What is the driving force for: P(aq) + P(aq) P2(aq) in pure water?
In the large scale regime it is enthalpic and entropic:
• ∆H < 0⇐= enthalpic penalty for solvating a hydrophobic surface due to loss of hydrogen bonds at the
interface
• ∆S > 0⇐= entropic penalty for solvating a hydrophobic surface due to ordering of interfacial waters
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Mechanism of Salting-In and Salting-Out
What is the driving force for: P(aq) + P(aq) P2(aq) in pure water?
In the large scale regime it is enthalpic and entropic:
• ∆H < 0⇐= enthalpic penalty for solvating a hydrophobic surface due to loss of hydrogen bonds at the
interface
• ∆S > 0⇐= entropic penalty for solvating a hydrophobic surface due to ordering of interfacial waters
In salt solutions:
The mechanism for Salting-In and Salting-Out can be inferred from
changes of ∆H and ∆S in salt solutions relative to pure water
∆∆G(q) = ∆Gsalt(q)− ∆Gwater
=⇒ Salting-Out ∆∆G < 0 Salting-In ∆∆G > 0
∆∆H(q) = ∆Hsalt(q)− ∆Hwater
∆∆S(q) = ∆Ssalt(q)− ∆Swater
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Mechanism of Salting-Out
0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4q [e]
-20
-10
0
10
20
30
40
∆∆G
(q)
[kJ/
mol
] Salting-OutSalting-In
0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4q [e]
-10
0
10
20
30
40
50
60
∆∆H
(q)
[kJ/
mol
] Salting-OutSalting-In
0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4q [e]
-20
-10
0
10
20
30
40
T∆∆
S(q
) [k
J/m
ol] Salting-OutSalting-In
For Salting-Out (high charge-density ions):∆∆G︸ ︷︷ ︸ = ∆∆H︸ ︷︷ ︸ − T∆∆S︸ ︷︷ ︸
negative positive negative
Thus, Salting-Out is purely an entropic effect
increases entropic penalty
P
PP
P
Salting-Out: is driven by elimination of an exclusion zone for the ions
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Mechanism of Salting-In (region-I)
0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4q [e]
-20
-10
0
10
20
30
40
∆∆G
(q)
[kJ/
mol
] Salting-OutSalting-In
0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4q [e]
-10
0
10
20
30
40
50
60
∆∆H
(q)
[kJ/
mol
] Salting-OutSalting-In
0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4q [e]
-20
-10
0
10
20
30
40
T∆∆
S(q
) [k
J/m
ol] Salting-OutSalting-In
For Salting-In (0.65 < |q| < 0.90 e):∆∆G︸ ︷︷ ︸ = ∆∆H︸ ︷︷ ︸ − T∆∆S︸ ︷︷ ︸
positive negative positive
Thus, Salting-In in this regime is an entropic effect
reduces entropic penalty
P
PP
P
Salting-In: the binding of ions reduces the ordering of the interfacial
water (entropic penalty) and, therefore, stabilizes the monomeric state.
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Mechanism of Salting-In (region-II)
0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4q [e]
-20
-10
0
10
20
30
40
∆∆G
(q)
[kJ/
mol
] Salting-OutSalting-In
0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4q [e]
-10
0
10
20
30
40
50
60
∆∆H
(q)
[kJ/
mol
] Salting-OutSalting-In
0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4q [e]
-20
-10
0
10
20
30
40
T∆∆
S(q
) [k
J/m
ol] Salting-OutSalting-In
For Salting-In (low charge-density ions):∆∆G︸ ︷︷ ︸ = ∆∆H︸ ︷︷ ︸ − T∆∆S︸ ︷︷ ︸
positive positive negative
Thus, Salting-In in this regime is an enthalpic effect
reduces enthalpic penalty
P
PP
P
Salting-In: the binding of ions reduces the enthalpic penalty
when the plates are solveted in water (acting as ‘surfactants’).
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Conclusions
-6.0 -5.0 -4.0 -3.0 -2.0 -1.0 0.0 1.0 2.0∆νions, pref (q)
-200.0
-190.0
-180.0
-170.0
-160.0
-150.0
-140.0
-130.0
∆G(q
) [k
J/m
ol]
salting-out
salting-in
exclusionbinding
entropic
entropic
enthalpic
• We did not find a correlation between the ion-induced changes of the structure (and
dynamics) between water molecules and the ability of these ions to alter the magnitude
of the hydrophobic interactions.
• However, we did observe that ∆G correlates with ∆νions, pref (depends on both ions
and solute) with 3 different slopes.
• From ∆∆H and ∆∆S we find the 3 slopes match 3 different mechanisms for the
salting effect.
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Acknowledgments
Bruce J. Berne (Columbia University)
Morten Hagen
Funding Agencies:
−→ International Reintegration Grant
−→ Start-Up Fund
Computer Facilities:
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