Co-evolution of Alpha-Helical Transmembrane Protein Residues

I am pleased to share that our comprehensive study on the evolutionary dynamics of membrane alpha-helical proteins has been published in the Journal of Molecular Evolution. The research is titled "Co-evolution of alpha-helical transmembrane protein residues: large-scale variant profiling and complete mutational landscape of 2277 known PDB entries representing 504 unique human protein sequences."

The paper details a large-scale analysis of 2277 high-resolution protein structures from the Protein Data Bank. To map the complete mutational landscape of these critical structural components, our team evaluated over 5.8 million predicted amino acid substitutions utilizing AlphaMissense libraries.

Our findings uncover a significant asymmetry in how polar and nonpolar amino acids evolve within transmembrane regions. The data indicates that nonpolar to polar changes generally correspond to higher pathological scores. However, specific substitutions, such as phenylalanine to tyrosine, present significantly lower pathological impacts. We also mapped key residue pairs that diverge from expected correlations, noting that valine to threonine substitutions via an alanine intermediate lower the statistical barrier of what would otherwise require multiple sequential base changes.

To better understand these pathways, we introduced models based on evolutionary game theory and applied partial correlation analysis to amino acid frequencies in homolog sequences. These mathematical frameworks suggest previously unrecognized evolutionary pressures that maintain functionality during sequence variation. We hope these insights provide a strong foundation for advancing membrane protein engineering and designing therapeutics that retain efficacy against drug resistance.

Karagöl, T., Karagöl, A., & Zhang, S. (2025). Co-evolution of alpha-helical transmembrane protein residues: large-scale variant profiling and complete mutational landscape of 2277 known PDB entries representing 504 unique human protein sequences. Journal of molecular evolution, 93(5), 581–599. https://doi.org/10.1007/s00239-025-10262-8