Motivation Accurately predicting the quantitative impact of a substitution on a protein's
molecular function would be a great aid in understanding the effects of observed genetic …

Over the past decades, the TIM‐barrel fold has served as a model system for the exploration
of how changes in protein sequences affect their structural, stability, and functional …

Understanding how each residue position contributes to protein function has been a long‐
standing goal in protein science. Substitution studies have historically focused on conserved …

Over the course of evolution, proteins families undergo sequence diversification via mutation
accumulation, with extant homologs often sharing less than 25% sequence identity. The …

Amino acid preferences vary across sites and time. While variation across sites is widely
accepted, the extent and frequency of temporal shifts are contentious. Our understanding of …

Predicting the functional impact of changes to biological sequences is a central challenge in
genetics and biology. Beyond genetics, sequence-to-function mapping has key applications …

Engineering a protein's stability improves its shelf life and expands its application
environment. Current studies of protein stability often involve predicting stability change from …

Epistasis is a common feature of genotype-phenotype maps. Understanding the patterns of
epistasis is critical for predicting unmeasured phenotypes, explaining evolutionary …

Protein evolution proceeds by a complex response of organismal fitness to mutations that
can simultaneously affect protein stability, structure, and enzymatic activity. To probe the …

The evolution of homologous and functionally equivalent multiprotein assemblies is
intriguing considering sequence divergence of constituent proteins. Here, we studied the …