Structure and Functions of Simple Peptides at Water-Membrane Interfaces

Andrew Pohorille and Christophe Chipot

Even the simplest protocell must have had the capability to catalyze the chemical reactions needed for its survival and growth, and to communicate with its environment. These functions must have been accomplished by simple molecules that could have been present in a protobiotic milieu. One such group of potential early catalysts and signaling molecules are peptides -- possible precursors of enzymes and receptors. Unfortunately, short peptides typically have disordered structures in aqueous solution and, therefore, do not appear to be suitable for the desired cellular functions. However, many of these peptides, depending on their sequence, can acquire a broad range of well defined secondary structures, such as alpha-helix, beta-strand or beta-turn, at water-membrane, water-oil or water-air interfaces. A crucial, common characteristic of these interfaces is that a nonpolar phase is adjacent to water.

The ability of small peptides to organize at aqueous interfaces was examined by performing a series of large-scale, molecular dynamics computer simulations of several peptides composed of two amino acids: nonpolar leucine (L) and polar glutamine (Q). The peptides differed in size and sequence of the amino acids. Among the molecules studied were the dipeptides LL, LQ, QL and QQ. Although these peptides were too short to form a secondary structure, they represented very good models for examining conformational preferences of the peptide backbone as a function of the sequence. The studies of L/Q peptides were extended to two heptamers, LQQLLQL and LQLQLQL, design to maximize interfacial stability of an alpha-helix and a beta-strand, respectively, by exposing polar side chains to water and nonpolar side chains to a nonpolar phase.

Finally, a transition of an undecamer, composed entirely of leucine residues, from a disordered structure in water to an alpha-helix in a nonpolar phase representing the interior of the membrane was investigated. Complete folding of a peptide in solution was accomplished for the first time in computer simulations. Images of the initial disordered structure and of an ordered structure can be found here.

The simulations revealed several basic principles governing the sequence-dependent organization of peptides at interfaces and thereby determining their ability to perform protocellular functions.

Short peptides tend to accumulate at interfaces and acquire ordered structures, providing that they have a proper sequence of polar and nonpolar amino acids. The specific identity of amino acids appears to be less important, a desirable protobiological property. The dominant factor determining the interfacial structure of peptides is the hydrophobic effect, which is manifested at aqueous interfaces as a tendency for polar and nonpolar groups of the solute to segregate into the aqueous and nonpolar phases, respectively. The resulting structures are called amphiphilic. Exceptions from this tendency were observed only when intramolecular hydrogen bonds were formed in the nonpolar phase without completely removing polar side chains from water, a unique feature of interfacial systems.

Based on results for folding the LQQLLQL heptamer to an alpha-helix at the water surface, it is proposed that, whenever possible, peptides fold at interfaces through a series of amphiphilic intermediates. Transitions between these intermediates involve changes not only in backbone angles but also in conformations of side chains. Once folded, the peptides form structures that are suitable for polymerization and have potential for catalytic activity.

If peptides consist of nonpolar residues only, they become inserted into the nonpolar phase. As demonstrated by the example of the leucine undecamer, such peptides fold into an alpha-helix as they partition into the nonpolar medium. The folding proceeds through an intermediate, called a 3₁₀-helix, which remains in equilibrium with the alpha-helix. Once in the nonpolar environment, the peptides can readily change their orientation with respect to the interface from parallel to perpendicular, especially in response to local electric fields. The ability of nonpolar peptides to modify both their structure and orientation with changing external conditions may have provided a simple mechanism of transmitting signals from the environment to the interior of a protocell.