Flexible Proteins at the Origin of Life

Abstract

Almost all modern proteins possess well-defined, relatively rigid scaffolds that provide structural preorganization for desired functions. Such scaffolds require the sufficient length of a polypeptide chain and extensive evolutionary optimization. How ancestral proteins attained functionality, even though they were most likely markedly smaller than their contemporary descendants, remains a major, unresolved question in the origin of life. On the basis of evidence from experiments and computer simulations, we argue that at least some of the earliest water-soluble and membrane proteins were markedly more flexible than their modern counterparts. As an example, we consider a small, evolved in vitro ligase, based on a novel architecture that may be the archetype of primordial enzymes. The protein does not contain a hydrophobic core or conventional elements of the secondary structure characteristic of modern water-soluble proteins, but instead is built of a flexible, catalytic loop supported by a small hydrophilic core containing zinc atoms. It appears that disorder in the polypeptide chain imparts robustness to mutations in the protein core. Simple ion channels, likely the earliest membrane protein assemblies, could also be quite flexible, but still retain their functionality, again in contrast to their modern descendants. This is demonstrated in the example of antiamoebin, which can serve as a useful model of small peptides forming ancestral ion channels. Common features of the earliest, functional protein architectures discussed here include not only their flexibility, but also a low level of evolutionary optimization and heterogeneity in amino acid composition and, possibly, the type of peptide bonds in the protein backbone.

Voltage vs. Ligand II: Structural insights of the intrinsic flexibility in cyclic nucleotide-gated channels

“…; and finally (5) When did the 6TM channels first appear? Our results suggest that the V-sensor and the pore domain were conceivably very flexible at the origin of life, which is consistent with recent findings on protein evolution [76,77]. Much of this flexibility was conserved in the family of CNG channels and diverged in very different ways within the VGIC superfamily, sharing a similar molecular architecture and developing diverse physiological properties.…”

The intramolecular hydrogen bonded–halogen bond: a new strategy for preorganization and enhanced binding

“… 4 Nature's proficiency continues to inspire synthetic studies “beyond the molecule,” as principles governing protein–ligand and protein–protein interactions are the same in synthetic systems. 5 – 9 Thus, developing new preorganization methods is valuable to all fields impacted by supramolecular chemistry. In this article, we introduce a novel strategy to preorganize structure and enhance halogen bonding (XBing)—the hydrogen bonded-halogen bond (HB–XB).…”

Intrinsically Disordered Proteins: The Dark Horse of the Dark Proteome

“…Furthermore, the archetype of primordial enzymes could be disordered beyond the molten globule state. For example, a small, evolved in vitro ligase does not contain a hydrophobic core or conventional elements of the secondary structure characteristic of modern water‐soluble proteins, but instead is built of a flexible, catalytic loop supported by a small hydrophilic core containing zinc atoms . Emerging evidence lends further support to the notion that even classical enzymes need not have a unique structure in order to be functional.…”

“…They formed the “feed stock” for the subsequent evolution to modern channels. Thus, in contrast to their modern descendants, simple ion channels, may have very likely been the earliest membrane protein assemblies that were flexible (disordered) but still retained their functionality …”