Molecular Modeling Of Protocellular Structures And Functions

Andrew Pohorille
Michael A. Wilson
Michael H. New
Christophe Chipot

NASA Ames Research Center
and
University of California, San Francisco

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

The organization of small peptides at aqueous interfaces, essential for catalytic activity and signaling, was examined in large-scale molecular dynamics simulations of several peptides composed of two amino acids, nonpolar leucine (L) and polar glutamine (Q). Based on results for the LQQLLQL heptamer, designed to maximize interfacial stability of an -helix by exposing polar side chains to water and nonpolar side chains to a nonpolar phase, it is proposed that, whenever possible, peptides fold at interfaces through a series of amphiphilic intermediates. 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 insert into the nonpolar phase. As demonstrated by the example of the leucine undecamer, such peptides fold into an -helix as they partition into the nonpolar medium. The folding proceeds through an intermediate, called 3-helix, which remains in equilibrium with the -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 the 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.

Another protocellular function the mechanism of which has been studied using molecular modeling is the activated formation of transmembrane proton gradient. This gradient could have driven chemical synthesis in the protocell. A simple, peptide-based model of a transmembrane proton pump consists of a proton source and two acceptors. The directionality of the pump is ensured by a ``gate-keeping'' mechanism involving a water molecule, conformational change of the primary acceptor or tautomerization of a histidine. The pump can be formed by two transmembrane peptide helices but not one helix.