An Introduction to Structural Phylogenetics for Biomedical Sciences

Structural phylogenetics offers a powerful framework for understanding the molecular basis of neural function and disease by combining evolutionary analysis with three-dimensional protein structure. While traditional protein-based phylogenetics relies mostly on amino acid sequences, recent advances in computational structure prediction have accelerated the integration of protein tertiary structures into phylogenetic studies. Since structure is more conserved than sequence, this approach may provide increased resolution in cases of high sequence divergence or mutational saturation, common issues in the study of complex, ancient, or fast-evolving protein families. In biomedical research, phylogenetics is a powerful approach for tracing the evolutionary origins and diversification of disease-related proteins. It provides a comparative framework to identify conserved structural motifs, function shifts, and predict potential targets for drug discovery and innovation. In neuroscience, these insights are especially valuable for uncovering the evolutionary basis of neural signaling, plasticity, and dysfunction. This chapter serves as a user-friendly practical tutorial for conducting structural phylogenetic analyses using accessible and computationally efficient tools, using synaptotagmins-calcium-sensing proteins essential for synaptic vesicle fusion-as a running example. This resource is designed for biomedical researchers seeking to integrate phylogenetics as a tool to build a comparative basis to strengthen their experimental design and improve their understanding of protein diversity and function.