what effects do salts have on biopolymers?. maxim v. fedorov 1, ingrid socorro 1, stephan schumm 2...
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What effects do salts have on biopolymers?
.
Maxim V. Fedorov1, Ingrid Socorro1, Stephan Schumm2 and Jonathan M. Goodman1
1 Unilever Centre for Molecular Science Informatics, Department of Chemistry, University of Cambridge, Cambridge, UK
2 Unilever R&D Vlaardingen, Vlaardingen, The Netherlands
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• Research: Biopolymers interactions with salts in
water.
• Systems: Water with salt and:
– Oligopeptides (3 - 21 amino acids)– Bee toxin (mellitin; 27 amino acids)
• Methods: Fully atomistic Molecular Dynamics simulations
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What effect do salts have on biopolymers?
- biopolymer solubility- biopolymer denaturation temperatures- enzyme activity- biopolymer swelling- growth rates of bacteria- stability of protein macroaggregates
Some of important processes are:
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Energetic optimization of mutual hydrogen bonded networks
The water hydrogen bonded network links secondary structures within the protein
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Water and cosolutes as ‘lubricants’ for protein folding.
Fully hydrated protein: the potential energy landscape is smoother
Schematic potential energy funnel for the folding of proteins without water: many barriers to the preferred minimum energy structure on the folding pathway
There are numerous local minima that might trap the protein in an inactive three-dimensional
molecular conformation
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Salt effects on biopolymer shapesD. Puett et al., JCP, 1967; H. Saito et al., Biopolymers, 1978; K. Zero & B.R. Ware, JCP, 1984;
Poly-L-Lysine, bulk water solution Poly-L-Lysine, NaCl solution
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Assembly of two oligopeptides in water
C. Muhle-Goll, et al., Biochemistry, 1994; P. Aymard, D. Durand & T. Nicolai, Int. J. Biol. Macromol.,1996
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Self-assembly to very stable amyloids
M. V. Fedorov et al Phys. A, 2006
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• Poly-L-Lysine (PLL), -Helix• Water solution (2300 water molecules)• Water and salt (2300 water and a few dozen NaCl molecules)
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Results: No Ions
RANDOM
COIL
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Comparison of two systemsPLL: no ions PLL: 0.50 M NaCl
Ramachandran density maps
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0.50 M NaCl
Na+ Cl-
HELIX
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Three major effects of ions
• Electrostatic screening (Debye-Hückel effect)
• Specific interactions by ion-pair formation (Electroselectivity effect)
• Salts affect water structure, which may change the hydrophobic interactions (Hofmeister effect)
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Hofmeister EffectIn 1888 Hofmeister observed that protein solubilities are influenced by the concentration and type of salts present. Solubilities tend to follow the general order:
- water activity - self-diffusion coefficient of water- viscosity of salt solutions- surface tension- lipid solubility of monoanions- polymer cloud points- polymer swelling
- protein solubility- protein denaturation temperatures- degree of protein aggregation - coacervate behaviour - critical micellar concentration- enzyme activity- growth rates of bacteria
SO42- < F- < Cl- < Br- < I- < SCN- < ClO4-
Other phenomena to follow the Hofmeister series:
precipitate, stabilize
Mg2+ < Na+ < K+ < Li+
solubilize, destabilize
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Electroselectivity (direct binding) effect
In 1990-1992 Goto and coworkers observed that conformation properties of some polypeptide and proteins solubilities are influenced by the concentration and type of 1:1 salts present following the electroselectivity series:
I- < Br- < Cl- < F-
precipitate, stabilize
F- < Cl- < Br- < I-
solubilize, destabilize
electroselectivity
Hofmeister
Inverse order with compare to the Hofmeister series for monovalent anions.
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Verification
• If the Debye-Huckel screening is important, the effect of various ions will be determined only by the ionic strength of solution
• If the electroselectivity is important, the effect of different ions should follow the electroselectivity series of the salts
• The importance of the Hofmeister effect can be determined by comparing the different ions with the Hofmeister series
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System
• Poly-L-Alanine 3 (PAA), -Helix (-57,-47). • ~1200 water molecules (TIP5P-E)• Li+, Na+, K+, Cs+ cations • F-, Cl-, Br-, I- anions.• OPLS/AA force-field• Periodic Boundary Conditions• Particle Mesh/Ewald electrostatics • BOX: 37 Å x 37 Å x 37 Å• Berendsen thermostat/barostat• GROMACS 3.3• Equilibration run: 27 ns, production run: 27 ns.
-
+
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How long shall we simulate?
Sampled part V of the available volume Vmax (volume of the box without the excluded volume of the tripeptide) visited be any of chlorine ions as a function of simulation time. This demonstrates equilibration time >> 1 ns as required for chlorines to visit any part of the box.
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Molecular Surfaces
• Dotted line: Solvent Accessible Surface (SAS)
• Solid line: molecular surface (MS)
• Shaded grey area: van der Waals surface
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Water accessible area
Compactconformations
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Water accessible area
NaF
NaI
NaCl
NaBr
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Ratio of compact conformations
WHY???
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Electroselectivity (direct binding) effect
I- < Br- < Cl- < F-
precipitate, stabilize
F- < Cl- < Br- < I-
solubilize, destabilize
electroselectivity
Hofmeister
Inverse order with compare to the Hofmeister series for monovalent anions.
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Possible ways of interactions: • Direct contacts:
• Shell – Shell contacts:
• Site – water – Site contacts:
+
-
-
+ -
-
++
+
-
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Direct Contact: fluorine anions
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Shell-shell interactions.
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Macroscopic Coulomb’s law doesn’t work on the molecular level.
• Macro Micro
0
( )macro
qU r
r
0
( )( )micro
qU r
F r r
F(r) – dielectric permittivity (screening factor). ( ) 1,F r r
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Visualization of the (a) electrostatic potential, (b) screening factor and (c) ion-hydrogen (- - -) and ion-oxygen ( --- ) RDF, created by a single charge anion/ cation (of radii a =1 A ) as functions of the distance from the surface of the sphere, R-a, which mimics the ion:.
MVF and A. A. Kornyshev, Mol. Phys., 2007, to be issued soon
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Potential of Mean Force
Activation Energy
Structure & Dynamics
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Peptide-water and ion-water PMFs
EIW
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Peptide –ion PMFsN-terminus C-terminus
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Peptide –ion PMFsSide chain groups Backbone groups
EPI
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Preferential Interaction
Cosolutes will change the chemical potential of a protein in a cosolvent solution compared to a pure solvent due to preferential interaction with or exclusion from the protein interface. 0 trG
The transfer from pure solvent to the cosolvent solution in unfavourable. The protein prefers to be surrounded by solvent molecules.
0 trGtransfer free energy:
solventprotein
cosolventproteintransferG
The protein prefers to be surrounded by cosolvent molecules
Protein Proteinwater
cosolvent
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Specific interactions of ions with polypeptide charges (local effects)
Preferential solvent / salt interactions (bulk effects)
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Conclusions• Salt effects on biopolymer solutions can be
reproduced “in silico” using the fully atomistic Molecular Dynamics simulations.
• Generally, ions contact biopolymers via an intermediate water shell.
• We can distinguish between the Debye-Hückel, Electroselectivity and Hofmeister effects for salts
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Acknowledgements
• Unilever R&D Vlaardingen
Robert Glen, Dmitry Nerukh ( Unilever Centre for Molecular Science Informatics, University of Cambridge, UK);Ruth Lynden-Bell (University of Belfast & University of Cambridge, UK);Alexei A Kornyshev (Imperial College London, UK);Gennady N Chuev (Institute of Experimental and Experimental Biophysics of RAS, Pushchino Biological Centre, Russia & University of Edinburgh, UK).
Financial Support