TMPfold: A Web Tool for Predicting Stability of Transmembrane α-Helix Association

• Published in: Journal of molecular biology Vol. 432; no. 11; pp. 3388 - 3394
• Main Authors: Lomize, Andrei L., Schnitzer, Kevin A., Pogozheva, Irina D.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15-05-2020
• Subjects: Amino Acid Sequence - genetics; Folding; Free energy; Humans; Internet; Membrane proteins; Mutation; Pathway; Protein Conformation, alpha-Helical; Protein Folding; Protein Structure, Secondary - genetics; Proteins - genetics; Proteins - ultrastructure; Software; Mutation; Pathway; Folding; Free energy; Membrane proteins
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2019.10.024

Estimating energies of transmembrane (TM) α-helix association is essential for understanding folding of membrane proteins and formation of their functional assemblies. A new physics-based method was developed and implemented in the TMPfold web server for the calculation of the free energy of TM helix association (ΔGasc) in TM α-bundles of known structure. The method was verified using the experimental ΔGasc values for 36 TM complexes, including dimers of 10 glycophorin A mutants. The calculated free energy changes (ΔΔGasc) caused by mutations in TM helices correlated with experimental changes in the stability of 42 mutants of bacteriorhodopsin and 25 mutants of rhomboid protease. TMPfold was applied for evaluation of ΔGasc in 554 PDB structures of 85 seven-helical TM proteins and identification of stable two-helical folding intermediates. The proposed tentative paths of cotranslational helix assembly of several polytopic proteins were consistent with experimental studies of their folding. TMPfold is accessible at (https://opm.phar.umich.edu/tmpfold_server).
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•Energetics of helix assembly offers insight into driving forces of membrane protein folding.•The TMPfold web server for calculating free energy of TM α-helix association was developed.•The method reproduces experimental helix association energies of native and mutant proteins.•TMPfold produces two-helical folding intermediates and tentative helix assembly pathways.•The web tool is useful for studying folding and stability of membrane proteins.