A Universal Molecular Clock of Protein Folds and Its Power in Tracing the Early History of Aerobic Metabolism and Planet Oxygenation

Abstract

The standard molecular clock describes a constant rate of molecular evolution and provides a powerful framework for evolutionary timescales. Here, we describe the existence and implications of a molecular clock of folds, a universal recurrence in the discovery of new structures in the world of proteins. Using a phylogenomic structural census in hundreds of proteomes, we build phylogenies and time lines of domains at fold and fold superfamily levels of structural complexity. These time lines correlate approximately linearly with geological timescales and were here used to date two crucial events in life history, planet oxygenation and organism diversification. We first dissected the structures and functions of enzymes in simulated metabolic networks. The placement of anaerobic and aerobic enzymes in the time line revealed that aerobic metabolism emerged about 2.9 billion years (giga-annum; Ga) ago and expanded during a period of about 400 My, reaching what is known as the Great Oxidation Event. During this period, enzymes recruited old and new folds for oxygen-mediated enzymatic activities. Remarkably, the first fold lost by a superkingdom disappeared in Archaea 2.6 Ga ago, within the span of oxygen rise, suggesting that oxygen also triggered diversification of life. The implications of a molecular clock of folds are many and important for the neutral theory of molecular evolution and for understanding the growth and diversity of the protein world. The clock also extends the standard concept that was specific to molecules and their timescales and turns it into a universal timescale-generating tool.

Evolutionary history of redox metal-binding domains across the tree of life

“…The multiple functions encoded by highly diverged protein families hinder testing the hypothesis of polyphyly via the application of a standard phylogenetic analysis with an associated protein evolution model (32). Furthermore, our analysis supports the hypothesis of extraordinary genetic innovation during the Archaean eon (19,33). One of these studies highlights genetic innovations during an "Archaean genetic expansion" that was associated with an expansion in microbial respiratory and electron transport capabilities (33).…”

“…This analysis suggests that enzymes recruited new (and preexisting) folds for oxygendependent metabolism in the several-hundred-million-year interval between the emergence of oxygenic photosynthesis and the GOE (19). The absence of connections between domain islands may reflect limitations of the sequence similarity-based bioinformatic approach used in this study.…”

“…One of these studies highlights genetic innovations during an "Archaean genetic expansion" that was associated with an expansion in microbial respiratory and electron transport capabilities (33). The other suggests that enzymes recruited new folds for oxygen-dependent metabolism (19). This "research and development" stage in the first ca.…”

A Dynamic Model for the Evolution of Protein Structure

“…However, [16] graphs the geological times of known structures, determined from independent archaeological evidence, against their normalized distance in nodes (nd) from the hypothetical ancestral structure at the base of a phylogenetic tree of structures. This relationship is linear, is presented in equations 2.6 and 2.7, where t is in gigayears, and is assumed to hold for all structures in the study.…”

“…When one takes the number of bifurcations leading to a particular structure and divides by the normalization one arrives at the normalized node distance (nd) of a node. The relation between t and nd for folds, as given in [16], was:…”