What effects do salts have on biopolymers?. Maxim V. Fedorov 1, Ingrid Socorro 1, Stephan Schumm 2...
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Transcript of What effects do salts have on biopolymers?. Maxim V. Fedorov 1, Ingrid Socorro 1, Stephan Schumm 2...
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
• 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
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:
Energetic optimization of mutual hydrogen bonded networks
The water hydrogen bonded network links secondary structures within the protein
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
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
Assembly of two oligopeptides in water
C. Muhle-Goll, et al., Biochemistry, 1994; P. Aymard, D. Durand & T. Nicolai, Int. J. Biol. Macromol.,1996
Self-assembly to very stable amyloids
M. V. Fedorov et al Phys. A, 2006
• Poly-L-Lysine (PLL), -Helix• Water solution (2300 water molecules)• Water and salt (2300 water and a few dozen NaCl molecules)
Results: No Ions
RANDOM
COIL
Comparison of two systemsPLL: no ions PLL: 0.50 M NaCl
Ramachandran density maps
0.50 M NaCl
Na+ Cl-
HELIX
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)
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
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.
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
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.
-
+
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.
Molecular Surfaces
• Dotted line: Solvent Accessible Surface (SAS)
• Solid line: molecular surface (MS)
• Shaded grey area: van der Waals surface
Water accessible area
Compactconformations
Water accessible area
NaF
NaI
NaCl
NaBr
Ratio of compact conformations
WHY???
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.
Possible ways of interactions: • Direct contacts:
• Shell – Shell contacts:
• Site – water – Site contacts:
+
-
-
+ -
-
++
+
-
Direct Contact: fluorine anions
Shell-shell interactions.
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
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
Potential of Mean Force
Activation Energy
Structure & Dynamics
Peptide-water and ion-water PMFs
EIW
Peptide –ion PMFsN-terminus C-terminus
Peptide –ion PMFsSide chain groups Backbone groups
EPI
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
Specific interactions of ions with polypeptide charges (local effects)
Preferential solvent / salt interactions (bulk effects)
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
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