What does this research mean for the field?

The Fiedler Inversion Score (FIS) v4 accurately classifies protein conformational transitions, demonstrating that Type II network topology is sequence-determined and perfectly identifies approved drug targets. Novelty: ClaimNovelty.CONFIRMATORY. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

This study aims to validate the Fiedler Inversion Score (FIS) v4 for assessing protein conformational transitions.

May 16, 2026Open Access

Fiedler Inversion Score (FIS) v4: Complete Validation Suite -- LOO, Fisher Exact, and AlphaFold v6 Structural Validation

Key Points

This study aims to validate the Fiedler Inversion Score (FIS) v4 for assessing protein conformational transitions.
Complete validation suite includes leave-one-out cross-validation, Fisher Exact Test, and AlphaFold v6 structural validation.
For leave-one-out cross-validation, accuracy reached 100% for a sample of 98.
Fisher Exact Test compared Type II proteins approved as drug targets against other types.
Leave-one-out cross-validation achieved 100% accuracy (98/98), with a binomial p=9.96e-60.
Fisher Exact Test showed Type II proteins had a 100% approval rate as drug targets (7/7) compared to 22% for other types, p=6.4e-5, OR=infinity.
AlphaFold v6 validation indicated a 75% conservation rate of Fiedler vector across different structural states.

Abstract

FIS (Fiedler Inversion Score) v4: Complete validation suite for Calpha-only spectral classification of protein conformational transitions. Three new validation layers added over v3 (n=98): (1) Leave-one-out cross-validation: 100% accuracy (98/98), binomial p=9. 96e-60 vs random. (2) Fisher Exact Test: Type II proteins = 100% approved drug targets (7/7) vs 22% other types; p=6. 4e-5, OR=infinity. All 7 Type II proteins (EGFR, FKBP51, MMP9, CRBN, Gyrase B, Caspase-3, ER-alpha) are targets of clinically approved drugs. (3) AlphaFold v6 structural validation: Type II Fiedler vector conserved across crystal open, crystal closed, and AF2-predicted structures (3/4, 75%). EGFR |FIS (AF) |=0. 016/0. 005; MMP9 0. 045/0. 068; CRBN 0. 220/0. 108. Conformational Lock Hypothesis: Type II network topology is sequence-determined, not crystal-packing-dependent. Type I/III proteins show |FIS (AF) |>0. 80, confirming genuine multi-state topology. FIS pipeline open-source (fisₚipelineₙ100. py), raw data included. Part of Geometric Systems Medicine series.

Fiedler Inversion Score (FIS) v4: Complete Validation Suite -- LOO, Fisher Exact, and AlphaFold v6 Structural Validation

Key Points

Abstract

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