Energy landscapes of peptide-MHC binding

Abstract

Molecules of the Major Histocompatibility Complex (MHC) present short protein fragments peptides on the cell surface, an important step in T cell immune recognition. MHC-I molecules process peptides from intracellular proteins; MHC-II molecules act in antigen-presenting cells and present peptides derived from extracellular proteins. Here we show that the sequence-dependent energy landscapes of MHC-peptide binding encode class-specific nonlinearities (epistasis). MHC-I has a smooth landscape with global epistasis; the binding energy is a simple deformation of an underlying linear trait. This form of epistasis enhances the discrimination between strong-binding peptides. In contrast, MHC-II has a rugged landscape with idiosyncratic epistasis: binding depends on detailed amino acid combinations at multiple positions of the peptide sequence. The form of epistasis affects the learning of energy landscapes from training data. For MHC-I, a low-complexity problem, we derive a simple matrix model of binding energies that outperforms current models trained by machine learning. For MHC-II, higher complexity prevents learning by simple regression methods. Epistasis also affects the energy and fitness effects of mutations in antigen-derived peptides (epitopes). In MHC-I, large-effect mutations occur predominantly in anchor positions of strong-binding epitopes. In MHC-II, large effects depend on the background epitope sequence but are broadly distributed over the epitope, generating a bigger target for escape mutations from T cell immunity than for MHC-I. Author SummaryT cell immunity involves the binding of short peptides to the intracellular MHC recognition machinery. Understanding how the binding energy depends on the peptide sequence is key to computationally predict immune recognition and immune escape evolution, for example, of pathogens and cancer cells. We find nonlinear energy landscapes that depend on the recognition pathway: smooth and easy to learn for MHC class I, rugged and difficult to learn for class II. Together, this work establishes links between biophysical origin, nonlinear structure, learnability from data, and biological implications for protein interaction landscapes.