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The structure and dynamics of a small enzyme capable of ligating two RNA fragments with the rate of 106 above background was fully characterized. This enzyme was evolved in vitro from a vast library of randomized proteins based on a scaffold. The enzyme does not resemble any contemporary protein. It consists of a flexible loop, a part of which is responsible for catalytic activity, a small, rigid core containing two zinc ions coordinated by neighboring amino acids and two highly flexible tails that might be of minor importance to the catalytic activity. In contrast to other zinc finger proteins this enzyme does not contain any ordered secondary structure elements such as helices or sheets. The ends of the loop are kept in direct proximity just through interactions of a charged residue and a histidine with a zinc ion, which they coordinate on the opposite side of the loop. Such a structure appears to be very fragile but, surprisingly, experiments and computer simulations of the original protein and its mutants indicate otherwise (see Fig. 1). The high flexibility of the protein facilitates its structural adjustments.

A similar picture emerges from studies of simple transmembrane channels that mimic those in ancestral cells. One such channel is an aggregation of an antiamoebin peptide that consists of only 16 amino acids. We found that this channel, in contrast to all known genomically coded, well-structured channels, is extremely flexible and does not form a conventional pore (Fig. 2). Yet it efficiently mediates ion transport.

Taken together, these results indicate that highly flexible proteins or protein assemblies that do not resemble their contemporary counterparts could carry out functions quite efficiently. These might be points on a continuous evolutionary trajectory that form the “missing link” between simple, but only weakly active, oligopeptides and well-folded proteins similar to those found in modern organisms.