Faithfulness of Potts-model landscape topology for mutational paths in overlapping genes

Ascertain how faithfully Direct Coupling Analysis Potts model energy landscapes recapitulate the detailed topology of the true protein fitness landscape for overlapping genes, particularly regarding the validity of functional mutational paths between independently generated overlapping sequences.

Background

The authors construct mutational paths connecting different overlapping-gene solutions while keeping both proteins functional according to the Potts energies and z-score thresholds. However, the validity of these paths depends critically on whether the Potts landscape accurately reflects the topology of the real fitness landscape, including higher-order epistasis.

Because Potts models capture only pairwise interactions, the authors caution that the topological faithfulness of these landscapes for overlapping genes is uncertain and requires empirical testing.

References

This is particularly true of mutational paths between overlapping proteins, whose validity requires that the Potts model faithfully recapitulate the detailed topology of the real fitness landscape . Given that Potts models do not account for any epistasis beyond second-order, this is unlikely to be true -- but how faithful an approximation it is remains to be tested.

— The fitness landscape of overlapping genes  (2604.00602 - Kirsch et al., 1 Apr 2026) in Discussion