One pocket, two poses: How sequence context shapes non-additive binding.

Specific peptide conformations and PIN1 residues are shown to generate non-additive recognition, linking statistical epistasis to molecular mechanisms across a complete sequence landscape.

• Why it matters: Non-additive binding is hard to explain mechanistically, and prior work often stops at statistical patterns without mapping them to concrete structural causes.
• What they did: Jiang et al. combined combinatorial mutagenesis, reference-independent epistasis analysis, binding assays, NMR, and molecular dynamics to connect sequence effects to peptide conformations and PIN1 residue behavior.
• The result: The integrated approach directly links statistical epistasis to molecular-level mechanisms, enabling interpretation of non-additive recognition across the full sequence landscape.

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