Getting to know each other: PPIMem, a novel approach for predicting transmembrane protein-protein complexes.

Because of their considerable number and diversity, membrane proteins and their macromolecular complexes represent the functional units of cells. Their quaternary structure may be stabilized by interactions between the α-helices of different proteins in the hydrophobic region of the cell membrane. Membrane proteins equally represent potential pharmacological targets par excellence for various diseases. Unfortunately, their experimental 3D structure and that of their complexes with other intramembrane protein partners are scarce due to technical difficulties. To overcome this key problem, we devised PPIMem, a computational approach for the specific prediction of higher-order structures of α-helical transmembrane proteins. The novel approach involves proper identification of the amino acid residues at the interface of molecular complexes with a 3D structure. The identified residues compose then nonlinear interaction motifs that are conveniently expressed as mathematical regular expressions. These are efficiently implemented for motif search in amino acid sequence databases, and for the accurate prediction of intramembrane protein-protein complexes. Our template interface-based approach predicted 21,544 binary complexes between 1,504 eukaryotic plasma membrane proteins across 39 species. We compare our predictions to experimental datasets of protein-protein interactions as a first validation method. The online database that results from the PPIMem algorithm with the annotated predicted interactions are implemented as a web server and can be accessed directly at https://transint.univ-evry.fr.

Biological interpretation of deep neural network for phenotype prediction based on gene expression.

BACKGROUND: The use of predictive gene signatures to assist clinical decision is becoming more and more important. Deep learning has a huge potential in the prediction of phenotype from gene expression profiles. However, neural networks are viewed as black boxes, where accurate predictions are provided without any explanation. The requirements for these models to become interpretable are increasing, especially in the medical field. RESULTS: We focus on explaining the predictions of a deep neural network model built from gene expression data. The most important neurons and genes influencing the predictions are identified and linked to biological knowledge. Our experiments on cancer prediction show that: (1) deep learning approach outperforms classical machine learning methods on large training sets; (2) our approach produces interpretations more coherent with biology than the state-of-the-art based approaches; (3) we can provide a comprehensive explanation of the predictions for biologists and physicians. CONCLUSION: We propose an original approach for biological interpretation of deep learning models for phenotype prediction from gene expression data. Since the model can find relationships between the phenotype and gene expression, we may assume that there is a link between the identified genes and the phenotype. The interpretation can, therefore, lead to new biological hypotheses to be investigated by biologists.