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This paper introduces ORBIT-FMIB, a framework combining Walsh-based decomposition and subset-conditioned dependence estimation to probe higher-order epistatic information retention in protein foundation models like ESM-2. While initial findings suggested a degradation of higher-order information, rigorous replication revealed this contrast to be unstable and sensitive to evaluation choices, indicating no robust evidence for selective loss. The study underscores the necessity of reproducibility checks for interpreting interaction structure findings from such models.
Protein foundation models may not selectively forget higher-order epistatic interactions, with initial findings of degradation proving unstable under replication.
Protein foundation models support mutation-effect and structural prediction, but predictive performance alone does not reveal which forms of biological interaction information remain accessible through model depth. We ask whether ESM-2 retains higher-order epistatic information as strongly as first- and second-order information across its representation hierarchy, introducing ORBIT-FMIB, a diagnostic framework combining Walsh-based interaction decomposition with subset-conditioned neural dependence estimation. The method is validated on synthetic landscapes with known interaction structure before being applied to the dense four-site GB1 fitness landscape using frozen ESM-2 representations. An initial production run suggested ESM-2 retains higher-order epistatic information less well than lower-order information ($\Delta_{\mathrm{HO-LO}}=-0.107$). An independent replication of the complete measurement grid, under matched GPU hardware and identical critic seeds, substantially reduced this contrast ($\Delta_{\mathrm{HO-LO}}=-0.017$), and its sign was unstable across otherwise-defensible evaluation-pairing choices applied to the same trained critics ($-0.011$ to $+0.015$). We therefore do not currently have robust evidence that ESM-2 selectively loses higher-order epistatic information, nor that retention is equal across orders; the directional question remains open. The measurement protocol itself, including its documented removal of a positional-subset shortcut in pooled critics, remains validated and is unaffected by this finding. ORBIT-FMIB is offered as a diagnostic framework for probing interaction structure in protein foundation models; this study's own replication result illustrates why such probing requires adequately-powered reproducibility checks before its output is treated as a biological finding.