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Hydrophobic Effect Hydrophobic Substances Hydrophobic substances are defined as substances that are readily soluble in many non-polar solvents, but only sparingly soluble in water, distinct from substances that have generally low solubility in all solvents because they form solids with strong intermolecular cohesion. The simplest hydrophobic substances include inert gases, hydrocarbons, and some other non-polar organic substances. (Tanford in "The Hydrophobic Effect", 2nd Ed, 1980).

Hydrophobic "Interaction" Upon placing a hydrophobic substance in water, water structure near the non-polar becomes more organized than that of a regular bulk water. Each hydrophobic molecule can not interact strongly with the water molecules, then water interact more with themselves via hydrogen bonding to form a more structured form around the apolar molecules. Water molecules form a cavity with the apolar molecules inside. These hydrates are quite stable. The heats of formation of hydrates are similar. (size-wise: Ar < CH4 < C2H6) Ar + 16 kcal/mol CH4 + 15 C2H6 + 15 This enthalpy change is not due to solvent - apolar molecule interaction, but to the energy released in organizing the water molecules into cage-like structure of similar size. ΔG = ΔH - TΔS ΔH (kcal/mol) ΔS (cal/deg mol) ΔG (kcal/mol) CH4 in benzene --> CH4 in H2O -2.8 -18 2.6 BIOS/CHEM 452 - Fung 2017 Fall - L4

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CH4 in CCl4 --> CH4 in H2O -2.5 -18 2.9 C2H6 in benzene --> C2H6 in H2O -2.2 -20 3.8 G is positive. CH4 or C2H6 will not be in H2O. H is negative. Energetically speaking, apolar molecules prefer water than an apolar solvent. The large negative S (from “less order” to more order”) in organizing water molecules cause the overall G to be positive and making the transfer unfavorable. One hydrophobic molecule in H2O: H2O molecules around it, in a more ordered form, with longer H-bond life time then that in bulk water. Two hydrophobic molecules in H2O: (1) H2O around each hydrophobic molecule (i.e. two ordered H2O network, or (2) H2O around one hydrophobic “lump” (of two molecules) (i.e. one ordered H2O network). Which is the case? (1) has larger negative S than (2), or (2) is more random than (1). So it is (2). The two hydrophobic molecules “lump” together, not because they have interactions, but because of the water entrophy. or

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For one hydrophobic molecule in water, it is surrounded by ordered water molecules. NO choice!

For three hydrophobic molecules in water, there is a choice, either each surrounded by ordered water molecules (left), or all three cluster together as a group to be surrounded by ordered water molecules (right). Which one has less “orderness” (higher entropy)?

In order to avoid positive ΔG, the apolar molecules cluster, form “aggregates” in water. Thus, the interaction that causes the apolar molecules to aggregate/associate is a hydrophobic effect. The driving force is entropic. The enthalpy change actually acts in opposition to this tendency. Therefore, ΔH > 0 when two or more apolar groups initially solvated, clump together in the interior of the protein. This means that an increase in temperature will tend to drive the equilibrium toward "hydrophobic bonding" (association) rather than toward dissociation. Because of its strength it was sometimes said that some sort of "hydrophobic bond" or “hydrophobic interaction” was responsible for this association. But it should be clear now that there is no bond, or not interaction associated with this mainly entropic phenomenon, which arises primarily from the structural rearrangement of water molecules in the overlapping solvation zones as many hydrophobic substances come together, and is therefore of longer range than any typical bond. Temperature Effects ΔG = ΔH - TΔS The higher the temperature, the larger the TS term in G, the stronger the hydrophobic effect. When H is positive, G is negative only when S is positive and large enough that TS term overbalances H. Regardless of the ultimate source of the entropy increase, processes which proceed spontaneously because of such BIOS/CHEM 452 - Fung 2017 Fall - L4

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large increase in entropy are defined as entropy driven processes. While most processes have negative values of H, are exothermic and enthalpy-drive, entropy-driven processes are not at all uncommon. The most common is the melting of ice at appropriate temperatures. In entropy-driven polymerization of some proteins, the assembly of dissolved molecules into large ordered structures of itself involves a decrease in entropy. The increase in entropy is due to solvent release during the process to provide the necessary disordering. This is demonstrated for the entropy-driven polymerization of tobacco mosaic virus protein. Bound water is released during polymerization. There is a slight increase in volume of the system. Molecular interactions - Non-covalent Interactions: Salt Bridges - Charge-charge interaction in proteins. Hydrogen Bonds - Mostly dipole-dipole interaction. Van der Waals Interaction - Instantaneous dipole - induced dipole interaction. Hydrophobic Effects - Entropy driven association. .

All these “interactions” are much weaker than covalent interactions (such as C-H bond, about 100 kcal/mol) or charge-charge interactions, but they could be “massive” and are important in systems containing biomolecules. Collectively they have a very significant influence on the three-dimensional structures of proteins, nucleic acids, polysaccharides, and membrane lipids. In aqueous solvent at 25 °C, the available thermal energy BIOS/CHEM 452 - Fung 2017 Fall - L4

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can be of the same order of magnitude as the strength of these weak interactions, and the interaction between solute and solvent (water) molecules is nearly as favorable as solute-solute interactions. Consequently, hydrogen bonds and ionic, hydrophobic, and van der Waals interactions are continually forming and breaking. Hydrophobic molecules Hydrophobic sequence Hydrophobic domains Hydrophobic moiety Found on the Web:

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2 | Water and Aqueous Solutions

© 2013 W. H. Freeman and Company

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CHAPTER 2 Water and Aqueous Solutions Learning goals: • • • • • • •

What kind of interactions occur between molecules Why water is a good medium for life Why nonpolar moieties aggregate in water How dissolved molecules alter properties of water How weak acids and bases behave in water How buffers work and why we need them How water participates in biochemical reactions

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Physics of Noncovalent Interactions Noncovalent interactions do not involve sharing a pair of electrons. Based on their physical origin, one can distinguish between: • Ionic (Coulombic) Interactions – Electrostatic interactions between permanently charged species, or between the ion and a permanent dipole • Dipole Interactions – Electrostatic interactions between uncharged, but polar molecules • van der Waals Interactions – Weak interactions between all atoms, regardless of polarity – Attractive (dispersion) and repulsive (steric) component • Hydrophobic Effect – Complex phenomenon associated with the ordering of water molecules around nonpolar substances BIOS/CHEM 452 - Fung Fall 2017 – L4

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Examples of Noncovalent Interactions

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The Hydrophobic Effect • Refers to the association or folding of nonpolar molecules in the aqueous solution • Is one of the main factors behind: – protein folding – protein-protein association – formation of lipid micelles – binding of steroid hormones to their receptors

• Does not arise because of some attractive direct force between two nonpolar molecules BIOS/CHEM 452 - Fung Fall 2017 – L4

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Solubility of Polar and Nonpolar Solutes

Why are nonpolar molecules poorly soluble in water? BIOS/CHEM 452 - Fung Fall 2017 – L4

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Low solubility of hydrophobic solutes can be explained by entropy • Bulk water has little order: – high entropy • Water near a hydrophobic solute is highly ordered: – low entropy

Low entropy is thermodynamically unfavorable, thus hydrophobic solutes have low solubility.

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Water surrounding nonpolar solutes has lower entropy

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Origin of the Hydrophobic Effect (1) • Consider amphipathic lipids in water • Lipid molecules disperse in the solution; nonpolar tail of each lipid molecule is surrounded by ordered water molecules • Entropy of the system decreases • System is now in an unfavorable state

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Origin of the Hydrophobic Effect (2) • Nonpolar portions of the amphipathic molecule aggregate so that fewer water molecules are ordered • The released water molecules will be more random and the entropy increases • All nonpolar groups are sequestered from water, and the released water molecules increase the entropy further • Only polar “head groups” are exposed and make energetically favorable H-bonds BIOS/CHEM 452 - Fung Fall 2017 – L4

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Hydrophobic effect favors ligand binding • Binding sites in enzymes and receptors are often hydrophobic • Such sites can bind hydrophobic substrates and ligands such as steroid hormones • Many drugs are designed to take advantage of the hydrophobic effect BIOS/CHEM 452 - Fung Fall 2017 – L4

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