Hydrophobic Surfaces in Two-faced (Janus) Molecules

Nature has excelled at utilizing noncovalent interactions and the hydrophobic effect to create macromolecules and molecular complexes. Such noncovalent intractions range from purely charge-charge interactions to hydrophobic effects, from hydrogen-bonding to van der Waals interaction, and from cation-π interaction to π-π stacking.

What is so intriguing is the finesse with which molecular components utilize such weak interactions to hold complexes together. For example, glucose is typically referred to as a hydrophilic solute. While glucose's high solublity in water follows from its hydrogen-bonding with water, glucose is also capable of forming complexes through the hydrophobic effect.

Another example is the DNA double helix. The two anti-parallel strands of DNA are held together by A–T and G–C base pairs. While the selectivity of these base pair interactions is controlled mainly by hydrogen-bonding, a limiting factor in utilizing hydrogen bonds in the base pairs lies in the fact that in aqueous solvents, the energies of the complementary base pair interactions are small. This is overcome by using both π-π stacking and hydrophobic effects to stabilize the double helix.

Like the Roman god Janus, the glucose molecule and the bases in DNA, adenine, thymine, guanine and cytosine, have "two faces." They can utilize both noncovalent interactions and the hydrophobic effect to form dynamic complexes. Let's begin with the bases uracil and thymine.

Hydration of Uracil and Thymine

The purine and pyrimidine bases found in nucleic acids are planar heterocyclic molecules which contain both proton acceptor and proton donor substituents and hydrogen-bonding interactions between them facilitates molecular recognition during biological information processing. The polar (hydrogen-bonding) groups are situated around the rim of the aromatic rings. The π-electron clouds are very nonpolar.

The two following models are based on quantum mechanics calculations. In both models, the state of lowest energy is a cooperative hydrogen-bonded configuration. The equilibria do not reveal a rigid hydration shell or cage which encapsulates the base. In aqueous solution, the surfaces of all solutes are indeed fully coated by water molecules, but in this case those states are higher in energy and more labile. It's important to remember that water molecules in the hydration shell of any solute, whether it's an ion, charged molecule, or a nonpolar solute such as methane, exchange with waters in the "regular" (bulk) water at high rates.

First, we see the hydration of uracil. Toggle between wireframe and spacefilling models. The wireframe model also displays hydrogen bonds, as calculated by JSmol.

Eleven waters form a stable hydrogen bond network around the edge of the base. Notice how water molecules avoid the "greasy" π-electron cloud of the aromatic ring.

Now we see the hydration of thymine. Toggle between wireframe and spacefilling models. The wireframe model also displays hydrogen bonds, as calculated by JSmol.

Again we see eleven waters in the "hydration shell." The methyl group of thymine prevents formation of a complete ring around the rim of the flat aromatic ring. Instead, we see a chain of hydrogen bonded water molecules spanning the nonpolar surface of the ring. This bridge is possible because steric crowding by the methyl group forces the two water molecules hydrogen bonded to the adjacent keto group away from the plane of ring. These two waters in turn serve as the abutment for the bridge across the nonpolar surface. Hence the hydrogen bonded bridge spanning the nonpolar face compensates for the weak attraction that water molecules have for nonpolar surfaces.