Distinct energetic blueprints diversify function of conserved protein folds
Malcolm L Wells1, Chenlin Lu1, Daniel Sultanov1
1Department of Biochemistry and Molecular Biophysics, Columbia University Irving Medical Center, New York, NY, USA.
Nature Chemistry
|June 5, 2026
Summary
Structural biology reveals conserved protein folds have diverse functions. Researchers mapped energetic landscapes of transcription factors and periplasmic binding proteins, finding unique
Area of Science:
- Structural biology
- Biochemistry
- Protein engineering
Background:
- Conserved protein folds can exhibit diverse biochemical functions.
- Understanding the link between protein structure, energy landscapes, and function is crucial.
Purpose of the Study:
- To investigate the energetic blueprints of bacterial transcription factors and periplasmic binding proteins.
- To determine if energy differences drive functional divergence despite conserved folds.
- To engineer novel protein functions through energy landscape manipulation.
Main Methods:
- Hydrogen exchange-mass spectrometry (HX-MS)
- Bioinformatics analysis
- X-ray crystallography
- Molecular dynamics simulations
- Rational protein redesign
Main Results:
- Identified distinct 'energetic blueprints' in homologous protein families with conserved folds.
- Demonstrated that these energy differences support unique functional requirements, even when binding similar ligands.
- Successfully engineered synthetic transcription factors with predictable ligand-induced transcriptional outputs via energy-driven design.
Conclusions:
- Decoding 'energetic blueprints' explains functional diversity in conserved protein folds.
- Protein energy landscapes offer a novel roadmap for rational protein design.
- This approach provides a distinct strategy for engineering proteins, including drug targets.
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