PT  - JOURNAL ARTICLE
AU  - David R. Bell
AU  - Serena H. Chen
TI  - Towards guided mutagenesis: Gaussian process regression predicts MHC class II antigen mutant binding
AID  - 10.1101/2021.04.14.439878
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.04.14.439878
4099  - http://biorxiv.org/content/early/2021/04/14/2021.04.14.439878.short
4100  - http://biorxiv.org/content/early/2021/04/14/2021.04.14.439878.full
AB  - Antigen-specific immunotherapies (ASI) require successful loading and presentation of antigen peptide into the major histocompatibility complex (MHC) binding cleft. One route of ASI design is to mutate native antigens for either stronger or weaker binding interaction to MHC. Exploring all possible mutations is costly both experimentally and computationally. To reduce experimental and computational expense, here we investigate the minimal amount of prior data required to accurately predict the relative binding affinity of point mutations for peptide-MHC class II (pMHCII) binding. Using data from different residue subsets, we interpolate pMHCII mutant binding affinities by Gaussian process (GP) regression of residue volume and hydrophobicity. We apply GP regression to an experimental dataset from the Immune Epitope Database, and theoretical datasets from NetMHCIIpan and Free Energy Perturbation calculations. We find that GP regression can predict binding affinities of 9 neutral residues from a 6-residue subset with an average R2 coefficient of determination value of 0.62 ± 0.04 (±95% CI), average error of 0.09 ± 0.01 kcal/mol (±95% CI), and with an ROC AUC value of 0.92 for binary classification of enhanced or diminished binding affinity. Similarly, metrics increase to an R2 value of 0.69 ± 0.04, average error of 0.07 ± 0.01 kcal/mol, and an ROC AUC value of 0.94 for predicting 7 neutral residues from an 8-residue subset. Our work finds that prediction is most accurate for neutral residues at anchor residue sites without register shift. This work holds relevance to predicting pMHCII binding and accelerating ASI design.Competing Interest StatementThe authors have declared no competing interest.