Speaker
Description
Proteins are often described by a single-funnel free-energy landscape leading to one native structure, yet metamorphic proteins reversibly interconvert between distinct folded states under physiological conditions. Lymphotactin (XCL1) is a striking example, exhibiting a chemokine-like monomeric fold and an alternative all-β dimeric fold whose equilibrium populations shift with temperature and salt concentration, implying an interplay between two native folds. Here, we developed a coarse-grained, dual-basin structure-based model to dissect how temperature, salt, and dimerization jointly control this fold switch. By tuning the relative strengths of monomer- and dimer-associated native contacts, we reproduce the qualitative experimental trend that the chemokine fold dominates at lower temperatures while the alternative dimer becomes increasingly populated near physiological temperatures, followed by unfolding at higher temperatures. To capture salt effects, we introduce an effective salt parameter that selectively rescales native contacts between charged residues, strengthening unlike-charge contacts and weakening like-charge contacts as screening is reduced; this produces a pronounced population shift toward the alternative fold and yields a temperature–salt phase diagram with a broad coexistence region where both folds are significantly populated. Analysis of charged-contact networks shows that the fold switch is characterized by a major redistribution of electrostatic contacts, including the formation of stabilizing unlike-charge interactions across the dimer interface. Finally, we extend the same framework to point mutations and reconstructed ancestral XCL1 variants, which have experimentally been shown to have different fold population propensities. We identify when charge-charge interactions are sufficient to explain fold-population trends and where additional sequence-dependent effects beyond native-charge contacts may be required.
| Keyword-1 | Metamorphic proteins |
|---|---|
| Keyword-2 | Protein fold switching |
| Keyword-3 | Lymphotactin Protein |