TMH Stab-pred: Predicting the stability of a-helical membrane proteins using sequence and structural features

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 structurebased parameters with free energy (& UDelta;G0) of & alpha;-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 multipleregression models to predict the stability of & alpha;-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 & UDelta;G0, 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.

Automated summary

In this study, the relationship between sequence and structure-based parameters and the free energy transfer of α-helical membrane proteins (TMPs) was examined. The results showed that several factors such as hydrophobic peptide transfer, relative contact order, total interaction energy, hydrogen bond count, and lipid accessibility of transmembrane regions play important roles in TMPs stability. Additionally, multiple regression models were developed to predict the stability of α-helical membrane proteins, achieving a correlation of 0.89 and mean absolute error (MAE) of 1.21 kcal/mol on a jack-knife test. Furthermore, a webserver for stability prediction was created and can be accessed freely at (https://web.iitm.ac.in/bioinfo2/TMHS/).