TMPfold

TMPfold predicts ΔGasc and ΔΔGasc for transmembrane (TM) α-helix associations to quantify stability and inform folding and assembly mechanisms of membrane proteins.

Key Features:

• Physics-Based Methodology: Employs a physics-based approach to estimate the free energy change (ΔGasc) of TM α-helix association within TM α-bundles.
• Verification and Validation: Validated by comparison with experimental ΔGasc values from 36 TM complexes, including glycophorin A dimers and mutants.
• Correlation with Experimental Data: Reproduces correlations between calculated ΔΔGasc due to mutations and experimental stability data from 42 bacteriorhodopsin mutants and 25 rhomboid protease mutants.
• Application on PDB Structures: Applied to calculate ΔGasc across 554 Protein Data Bank (PDB) structures of 85 seven-helical TM proteins to identify stable two-helical folding intermediates.
• Cotranslational Helix Assembly Pathways: Provides tentative cotranslational helix assembly pathways in several polytopic proteins consistent with experimental folding studies.

Scientific Applications:

• Membrane Protein Folding Studies: Quantifies TM helix association energetics to elucidate folding mechanisms and identify folding intermediates.
• Functional Assembly Analysis: Assesses stability of helix–helix interactions to inform analysis of functional assembly in membrane protein complexes.
• Mutation Impact Assessment: Predicts ΔΔGasc effects of mutations to evaluate impacts on TM helix stability in glycophorin A, bacteriorhodopsin, rhomboid protease and other membrane proteins.

Methodology:

Computes physics-based estimates of ΔGasc and ΔΔGasc for TM α-helix associations from known structures and PDB models (applied to 554 PDB structures of 85 seven-helical TM proteins) and validates results by comparison to experimental ΔGasc values from 36 TM complexes and mutation datasets (42 bacteriorhodopsin and 25 rhomboid protease mutants).