Summary
Coevolutionary patterns in multiple sequence alignments do not contribute to accurate modeling of protein-protein interactions (1,2). Instead, correct docking appears to be driven by interactions (unlike for protomers), which are more susceptible to disruption by mutations. One study found that the best way to improve PPI structure prediction is to make the MSAs of each individual protomer deeper(2). This contrasts with observations made for small molecules.
Figures
Figures from (1)
1.
Li S, Mu Z, Yan C. Dissecting the Black Box of AlphaFold in Protein–Protein Complex Assembly. openRxiv; 2026. Available from: https://doi.org/10.64898/2026.04.03.716280
2.
Luo Y, Wang W, Peng Z, Yang J. Benchmarking MSA pairing for protein-protein complex structure prediction reveals a depth-over-pairing principle. 2026 Apr; Available from: http://dx.doi.org/10.64898/2026.04.14.718427