Modeling and Inference of Sequence-Structure Specificity

In order to evaluate protein sequences for simultaneous satisfaction of evolutionary and physical constraints, this paper develops a graphical model approach integrating sequence information from the evolutionary record of a protein family with structural information based on a molecular mechanics force field. Nodes in the graphical model represent choices for the backbone (native vs. non-native), amino acids (conservation analysis), and side-chain conformations (rotamer library). Edges capture dependence relationships, in both the sequence (correlated mutations) and the structure (direct physical interactions). The sequence and structure components of the model are complementary, in that the structure component may support choices that were not present in the sequence record due to bias and artifacts, while the sequence component may capture other constraints on protein viability, such as permitting an efficient folding pathway. Inferential procedures enable computation of the joint probability of a sequence-structure pair, thereby assessing the quality of the sequence with respect to both the protein family and the specificity of its energetic preference for the native structure against alternate backbone structures. In a case study of WW domains, we show that by using the joint model and evaluating specificity, we obtain better prediction of foldedness of designed proteins (AUC of 0.85) than either a sequence-only or a structure-only model, and gain insights into how, where, and why the sequence and structure components complement each other.