The folding and stability of transmembrane proteins (TMPs) are governed by the insertion of secondary structural elements into the cell membrane followed by their assembly. Understanding the important features that dictate the stability of TMPs is important for elucidating their functions. In this work, we related sequence and structure-based parameters with free energy (ΔG0) of α-helical membrane proteins. Our results showed that the free energy transfer of hydrophobic peptides, relative contact order, total interaction energy, number of hydrogen bonds and lipid accessibility of transmembrane regions are important for stability. Further, we have developed multiple-regression models to predict the stability of α-helical membrane proteins using these features and our method can predict the stability with a correlation and mean absolute error (MAE) of 0.89 and 1.21 kcal/mol, respectively, on jack-knife test. The method was validated with a blind test set of three recently reported experimental ΔG0, which could predict the stability within an average MAE of 0.51 kcal/mol. Further, we developed a webserver for predicting the stability and it is freely available at (https://web.iitm.ac.in/bioinfo2/TMHS/). The importance of selected parameters and limitations are discussed.
Keywords: Free energy; Membrane proteins; Structure and sequence-based features; Thermodynamic stability; Transmembrane.
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