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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

– Typeset by FoilTEX –

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?

– Typeset by FoilTEX – 1

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


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 0.6 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


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


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


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


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?


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)


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


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


Potential Energy

no-ions Hydrogen Bond Energy

R. Zangi, J. Phys. Chem B. 114, 643 (2010)


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]


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.


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 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


Binding/Exclusion of the Ions and Water


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

)


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


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


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


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


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


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


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


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


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.


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


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


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


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’).


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.


Acknowledgments

Bruce J. Berne (Columbia University)

Morten Hagen

Funding Agencies:

−→ International Reintegration Grant

−→ Start-Up Fund

Computer Facilities:


chaotropes & kosmotropes and the driving force … · chaotropes & kosmotropes and the...

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