Study unveils mutation map for protein binding evolution

Researchers detailed a method for tracing the mutation-driven evolution of protein binding pairs, showing that a few key changes can lead to significant functional shifts guided by positive selection. The study by Ziv Avizemer, Carlos Martí‐Gómez and three others was published on April 20.

The study delves into the evolution of protein binding pairs, particularly those with extreme specificities, a process primarily driven by single-point mutations. These pairs evolve by acquiring mutations that enhance their affinity beyond a functional threshold, isolating them from their homologs. According to the study, the research addresses a critical evolutionary puzzle: How new specificities emerge while retaining necessary affinity at each stage of mutation. Previously, connecting two orthogonally paired proteins through a functional mutation path was only feasible when these pairs were closely related mutationally. This study, however, explores this process in pairs with significant mutational differences.

According to the study, the researchers introduced an atomistic and graph-theoretical approach to identify potential paths of single mutations with low molecular strain, connecting two distinct protein pairs. They applied this methodology to two bacterial colicin endonuclease-immunity protein pairs, separated by 17 interface mutations. While initially unable to find a functional mutation path without strain between these two pairs, they succeeded by considering additional mutations that bridge amino acids not directly interchangeable through single-nucleotide mutations. The study states that this approach led to discovering a viable 19-mutation trajectory, functional in vivo. Remarkably, the switch in specificity was abrupt, triggered by a single significant mutation in each protein, underscoring the role of key mutations in driving functional divergence.

According to the study, the research not only demonstrates the feasibility of tracing the evolutionary paths of protein binding pairs but also sheds light on the mechanism of their functional divergence. It highlights how certain mutations, while long in sequence, can result in sudden and significant changes in protein functionality. These mutations not only adapt to their host but also provide a selective advantage, illustrating the role of positive Darwinian selection in functional evolution. This research, the study states, sets a precedent for the use of energy-based modeling to understand the evolution of protein binding pairs, potentially offering insights into microbial resistance mutations and the development of new enzyme activities.

Research Square: Ziv Avizemer et al., Evolutionary paths that link orthogonal pairs of binding proteins (2023). https://doi.org/10.21203/rs.3.rs-2836905/v1