Speaker
Description
Metamorphic proteins are an unusual class of proteins capable of adopting more than one stable native fold, challenging the classical assumption that a single amino acid sequence encodes a single structure. In this work, we investigate the folding behaviour of three closely related proteins: B4, SB3, and the engineered mutant SB4. Despite differing by only a small number of residues, these proteins populate distinct structural states experimentally, with SB4 in particular exhibiting the ability to switch between a B-like fold and an S-like fold.
To probe the mechanisms underlying this fold-switching behaviour, we employ a coarse-grained Cα structure-based model combined with Langevin dynamics. In this framework, each amino acid is represented by a single bead, and native interactions are encoded through structure-based contact potentials, enabling efficient exploration of protein folding energy landscapes. By varying temperature and the relative strengths of native contacts associated with the B- and S-folds, we simulate the folding of B4, SB3, and SB4. The resulting trajectories are analysed using RMSD-based order parameters, native-contact fractions, and free-energy surface projections.
The simulations reproduce the expected two-state folding behaviour of B4, reveal a more complex energy landscape for SB3 consistent with the presence of an intermediate state, and demonstrate that SB4 can populate both the B- and S-folds depending on model parameters. These results show that simplified coarse-grained models can capture key features of metamorphic protein folding and provide insight into how minimal sequence changes reshape the underlying energy landscape. The findings complement recent experimental studies and contribute to a deeper understanding of the physical basis of protein fold switching.
| Keyword-1 | Protein folding |
|---|---|
| Keyword-2 | Metamorphic protein |
| Keyword-3 | Computational biophysics |