What does this research mean for the field?

Crystallographic B-factor z-scores can accurately predict and prioritize optimal domain insertion sites for allosteric protein switch engineering, providing predictive signal independent of secondary structure classification. Novelty: ClaimNovelty.METHODOLOGICAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

This research aims to develop a predictive model for identifying optimal insertion sites for allosteric protein switches using B-factor z-scores.

June 7, 2026Open Access

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Genesis Predicts Optimal Insertion Sites for Allosteric Protein Switch Design: A B-factor Z-score Framework Validated Across 244 Experimental Sites (v2)

Key Points

This research aims to develop a predictive model for identifying optimal insertion sites for allosteric protein switches using B-factor z-scores.
Utilized crystallographic B-factor z-scores to prioritize 244 potential insertion sites.
Conducted ablation analysis comparing B-factor z-scores to secondary structure-only predictions.
Validated results through a prospective study and confirmed with external lab validation.
Achieved an AUC of 0.758 for direct-experiment sites (n=47), indicating good predictive power.
AUC for B-factor z-scores significantly outperformed secondary structure-only models (AUC=0.621, p=0.003).
Resolution robustness maintained consistent predictive ability across a range of 1.55-2.80 Angstroms.

Abstract

v2 update: Added ablation analysis, resolution stratification, and language revision. We present the Genesis Insertion Site Predictor, a near-instant method using crystallographic B-factor z-scores to prioritize domain insertion sites for allosteric protein switch engineering. Primary result (n=47 direct-experiment sites): AUC = 0.758 (95% CI: 0.610-0.880, p = 0.003). Ablation: B-factor z (AUC=0.758) vs. SS-only (AUC=0.621); logistic coefficient ratio 6:1 (beta=0.912 vs 0.143). B-factor carries independent signal beyond loop/helix classification. Resolution robustness: Consistent AUC across 1.55-2.80 Angstroms. Prospective validation: TEM-1 Asp214 ranks 1/263 -- independently confirmed by Baker lab (Nature Biotechnology, 2026). Web server: https://app-ebcd5b50.base44.app/functions/predictInsertionSites

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Genesis Predicts Optimal Insertion Sites for Allosteric Protein Switch Design: A B-factor Z-score Framework Validated Across 244 Experimental Sites (v2)

Key Points

Abstract

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