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

Growing cells invest a significant part of their biosynthetic capacity into the production of
proteins. To become functional, newly-synthesized proteins must be N-terminally processed …

Protein language models (pLMs) have emerged as potent tools for predicting and designing
protein structure and function, and the degree to which these models fundamentally …

This article is dedicated to the memory of Michael G. Rossmann. Dating back to the last
universal common ancestor, P-loop NTPases and Rossmanns comprise the most ubiquitous …

Since 1992, all state-of-the-art methods for fast and sensitive identification of evolutionary,
structural, and functional relations between proteins (also referred to as “homology …

The vast majority of theoretically possible polypeptide chains do not fold, let alone confer
function. Hence, protein evolution from preexisting building blocks has clear potential …

Mechanisms of emergence and divergence of protein folds pose central questions in
biological sciences. Incremental mutation and stepwise adaptation explain relationships …

Although homologous protein sequences are expected to adopt similar structures, some
amino acid substitutions can interconvert α-helices and β-sheets. Such fold switching may …

The noncoding genome plays an important role in de novo gene birth and in the emergence
of genetic novelty. Nevertheless, how noncoding sequences' properties could promote the …

The emergence of novel proteins, beyond these that can be readily made by duplication and
recombination of preexisting domains, is elusive. De novo emergence from random …