Highlights•In-depth sequence analysis reveals that the protein fold universe is more
evolutionarily connected than previously assumed.•Short ancestral fragments are observed …

Highlights•Folding stability is an important factor for evolution and provides a negative
selection pressure.•Evolution re-shuffles flexibilities to fine-tune function, thereby modulating …

Conformational flexibility plays a critical role in enzyme function and regulation.
Conformational changes, which can occur on multiple length and time scales, facilitate, for …

Glycosidases are phylogenetically widely distributed enzymes that are crucial for the
cleavage of glycosidic bonds. Here, we present the exceptional properties of a putative …

Enzymes catalyze the chemical reactions of life. For nearly half of known enzymes, catalysis
requires the binding of small molecules known as cofactors. Polypeptide-cofactor complexes …

Natural proteins are frequently marginally stable, and an increase in environmental
temperature can easily lead to unfolding. As a result, protein engineering to improve protein …

Thioredoxins (TRXs) are ubiquitous disulfide oxidoreductases structured according to a
highly conserved fold. TRXs are involved in a myriad of different processes through a …

Paralogous proteins play a vital role in evolutionary adaptation of organisms and species
divergence. One outstanding question is the molecular basis for how folding mechanisms …

Many metabolites are generated in one step of a biochemical pathway and consumed in a
subsequent step. Such metabolic intermediates are often reactive molecules which, if …

Obligate symbionts typically exhibit high evolutionary rates. Consequently, their proteins
may differ considerably from their modern and ancestral homologs in terms of both …