Learning Sequence Determinants of Protein:protein InteractionSpecificity with Sparse Graphical Models

摘要

In studying the strength and specificity of interaction between members of two protein families, key questions center on which pairs of possible partners actually interact, how well they interact, and why they interact while others do not. The advent of large-scale experimental studies of interactions between members of a target family and a diverse set of possible interaction partners offers the opportunity to address these questions. We develop here a method, DgSpi (Data-driven Graphical models of Specificity in Protein:protein Interactions), for learning and using graphical models that explicitly represent the amino acid basis for interaction specificity (why) and extend earlier classification-oriented approaches (which) to predict the ΔG of binding (how well). We demonstrate the effectiveness of our approach in analyzing and predicting interactions between a set of 82 PDZ recognition modules, against a panel of 217 possible peptide partners, based on data from MacBeath and colleagues. Our predicted ΔG values are highly predictive of the experimentally measured ones, reaching correlation coefficients of 0.69 in10-fold cross-validation and 0.63 in leave-one-PDZ-out cross-validation.Furthermore, the model serves as a compact representation of amino acidconstraints underlying the interactions, enabling protein-levelΔG predictions to be naturally understood in termsof residue-level constraints. Finally, as a generative model,DgSpi readily enables the design of new interactingpartners, and we demonstrate that designed ligands are novel and diverse.