Enzyme engineering is an important biotechnological process capable of generating
tailored biocatalysts for applications in industrial chemical conversion and biopharma …

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

INTRODUCTION Enzymes possess extraordinary catalytic proficiency and specificity. These
properties ultimately derive from interactions not just between the active-site residues and …

A protein's genetic architecture–the set of causal rules by which its sequence produces its
functions–also determines its possible evolutionary trajectories. Prior research has …

The rate of protein synthesis is slower than many folding reactions and varies depending on
the synonymous codons encoding the protein sequence. Synonymous codon substitutions …

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 …

The construction of custom libraries is critical for rational protein engineering and directed
evolution. Array‐synthesized oligo pools of thousands of user‐defined sequences (up to∼ …

The distribution of fitness effects of mutation plays a central role in constraining protein
evolution. The underlying mechanisms by which mutations lead to fitness effects are …

When amino acids vary during evolution, the outcome can be functionally neutral or
biologically‐important. We previously found that substituting a subset of nonconserved …

Many eukaryotic membrane proteins are prone to misfolding, which compromises their
functional expression at the plasma membrane. This is particularly true for mammalian …