Opening image: Computer simulation of a DPC micelle. The hydrocarbon chains are colored green, while the hydrophilic headgroups are shown in CPK colors. Data courtesy of Peter Tieleman [J. Phys. Chem. 104: 6380-6388 (2000)].

Introduction

Amphiphilic molecules, commonly called "amphiphiles", are molecules with parts having affinities for water and organic solvents.

Most detergents are amphiphiles, molecules with a polar headgroup and a long hydrocarbon tail. The important characteristic that distinguishes amphiphilic molecules from two-faced or Janus molecules (see previous tutorial) is that amphiphiles tend to self-organize: amphiphilic molecules will associate to form stable aggregates involving both polar interactions with water and the hydrophobic effect.

For example, amphiphiles may form micelles, spherical particles with a nonpolar interior while the surface interacts with the surrounding water. Two-faced molecules like cyclodextrin are smaller molecules in which the parts differing in polar and nonpolar character are not immediately evident; they have is no tendency to self-assemble in the absence of other components.

Self-Assembly

Micelle formation nicely illustrates two important concepts: the hydrophobic effect, and self-assembly.

The term self-assembly refers to the process whereby pre-existing components spontaneously organize or assemble into more complex objects, typically through collisions in solution until a stable structure of minimum energy is reached. Molecular self-assembly involves noncovalent interactions (van der Waals, electrostatic, hydrogen bonds, etc.) and the hydrophobic effect. Finally, self-assembly reflects information encoded (as shape, charge, dipoles, hydrogen bond donors and acceptors, etc.) in individual components; these characteristics determine the interactions among the components.

Design of an Amphiphilic Molecule

Micelle formation is determined by the physical and chemical properties of the hydrophobic and hydrophilic groups, respectively. The size and shape of the hydrocarbon moiety and the size, charge, and hydration of the hydrophilic head group are of utmost importance in this respect. The driving force behind the association is the reduction in the free energy of the system.

Let's begin with dodecane, C₁₂H₂₆. This hydrocarbon is absolutely insoluble in water. Its melting and boiling points are -9.6°C and 216°C, respectively. Suppose we have a teflon-lined tray and fill it part way with pure water. Next we carefully place a drop of chloroform containing 54 molecules of dodecane on the surface. The chloroform evaporates quickly, and the dodecane molecules which initially were scattered on the surface come together to form a spherical droplet on the surface. Does the droplet form because of the hyrophobic effect? No. The dodecane molecules were never surrounded by hydration shells. The driving force for droplet formation is simply van der Waals forces between the oil molecules. The equilibrium state is a ball because that shape has the smallest surface area to volume ratio, i.e., the lowest free energy.

A droplet of dodecane containing 54 molecules. Toggle space-filling model.

Actually, the model is the hydrocarbon interior of a dodecylphosphocholine (DPC) micelle. Only the carbon backbone is displayed; the hydrogens are hidden.

The molecular dynamics simulation was carried out with 54 molecules of DPC and several thousand water molecules in a box. The temperature is raised to 25°C and the atomic coordinates for all the molecules in the box are sampled every picosecond until equilibrium is reached.

Is there a way to drag the hydrocarbon chain into water? The solubility of 1-dodecanol is 2 μM, so that isn't a satisfactory way to get the hydrocarbon chain into water. However, if we add a phosphocholine group the solubility will be large.

Computer Simulation of a Micelle

Dodecylphosphocholine is an amphiphile. The phosphate is bonded to two alcohols. One is 1-dodecanol and the other is choline. The alkyl group is commonly called "dodecyl," instead of "dodecanyl." Choline is a 2-carbon unit containing a nitrogen bonded to three methyl groups. The nitrogen with its four bonds has a permanent positive charge. However, the methyl groups weaken the interaction of the positive charge with the water dipole.

The phosphocholine group is the polar headgroup, and the dodecyl group is the nonpolar tail.

Toggle between an energy-minimized model of DPC in a solvent-free environment and the original model of DPC found within a micelle. The choline trimethylammonium group is always as close as possible to the one of the negatively charged oxygen atoms of the phosphate. This is indeed a very strong charge-charge interaction in the absence of water. Toggle space-filled model.

Now let's look at the results of Tieleman's molecular dynamics study of dodecylphosphocholine micelles.

Snapshot of a DPC micelle. For clarity the water molecules are omitted. However, without the presence of water, the computer simulation would meaningless, since the micelle structure is due to the interactions of the amphiphilic DPC molecules with water. Toggle space-filling model.

Color the hydrocarbon chains are green. Look carefully at the phosphocholine headgroups. Some project out into the solvent, but others adopt a conformation which brings the positively charged nitrogen close to the negatively charged phosphate.

Micelles are very dynamic. The phosphate group acts like a swivel, allowing the phosphocholine headgroup to spin and wag freely. These motions are indeed very rapid, so that the phosphocholine headgroup sweeps out a large cone at the surface of the micelle. Consequently, the "exposed" nonpolar patches in the static model are likely to be buried most of the time, either by the headgroup or by intermingling with other hydrocarbon tails.

Given the dynamic nature of micellar structures, the number of amphiphilic molecules depends primarily on two factors: the length of the hydrocarbon chain, and the size and charge of polar headgroup. For a DPC micelle, a balance is reached when the nonpolar interior is large enough to accommodate the space required by the phosphocholine headgroups. If you examine the model carefully and imagine the cones swept out by each phosphocholine headgroup, it becomes clear that steric clashes between headgroups impose a restriction on the number of DPC molecules in the micelle.

Eleven DPC molecules from the micelle. Note the diverse conformations of the hydrocarbon chains. The interior of the micelle is indeed a liquid, as expected from the melting point of dodecane. Toggle spacefill.

Although the computer simulation involved thousands of water molecules, let's look at only those water molecules within 5.0 Å of the DPC molecules.

Over 1100 water molecules are within 5 Å of the DPC molecules. This represents the hydration shell of the micelle. Water molecules leave and enter the hydration layer on a picosecond time scale. Toggle water as ball-and-stick or spacefilling.

Toggle slab mode. Note that no matter how you rotate the slab, you can't find any water molecules in the interior of the micelle. All the hydrocarbon chains intermingle and stay in van der Waals contact with each other.

The Hydration of One DPC Molecule

Molecule number 49, chosen from the 54 molecules in the micelle because its polar headgroup projects into the surrounding solvent.

Show water molecules that are hydrogen bonded to the oxygen atoms of the phosphate. Toggle water as ball-and-stick (with hydrogen bonds) or spacefill.

Additional water molecules comprise the hydration shell of the -CH₂CH₂N(CH₃)₃⁺ group of DPC-49. The hydrogen bonding is stronger than the interaction of the positive charge with the dipoles of the water molecules.

Complete hydration shell of DPC-49. Several waters are within van der Waals distance of the hydrocarbon chain.