Analyzing \b{eta}-Lactamase Evolution from the Principle of Least Action Perspective

Protein sequences change over time due to the accumulation of mutations in the genes that encode them.

Nonetheless, accurately identifying the most probable evolutionary pathways and more efficient trajectories between an ancestral and a derived sequence remains a challenge.

This difficulty stems from a limited understanding of the critical factors that drive the evolutionary process.

This study aims to address this issue by validating a newly proposed mechanistic model (grounded on the principle of least action) for analyzing protein evolution, using beta-lactamase as an empirically characterized evolutionary model.

The initial findings indicate that, after accounting for how mutations and the context-dependent interactions between them (epistasis) affect protein stability and, hence, the kinetics of protein folding, a resort to the principle of least action allows us to simultaneously identify the most probable pathways and the most efficient trajectories swiftly and accurately.

These findings also suggest that the most probable evolutionary protein pathways are the ones that exhibit the most efficient trajectories.

All in all, our study addresses several unanswered questions regarding the main factors that govern how protein evolves at the molecular level (under constant selection pressure) and outlines directions for future research in key fields such as directed evolution and ancestral sequence reconstruction.