Quantum chemical analysis explains hemagglutinin peptide-MHC Class II molecule HLA-DRβ1*0101 interactions

We present a new method to explore interactions between peptides and major histocompatibility complex (MHC) molecules using the resultant vector of the three principal multipole terms of the electrostatic field expansion. Being that molecular interactions are driven by electrostatic interactions, we applied quantum chemistry methods to better understand variations in the electrostatic field of the MHC Class II HLA-DRβ1*0101-HA complex. Multipole terms were studied, finding strong alterations of the field in Pocket 1 of this MHC molecule, and weak variations in other pockets, with Pocket 1 ≫ Pocket 4 > Pocket 9 ≈ Pocket 7 > Pocket 6. Variations produced by "ideal" amino acids and by other occupying amino acids were compared. Two types of interactions were found in all pockets: a strong unspecific one (global interaction) and a weak specific interaction (differential interaction). Interactions in Pocket 1, the dominant pocket for this allele, are driven mainly by the quadrupole term, confirming the idea that aromatic rings are important in these interactions. Multipolar analysis is in agreement with experimental results, suggesting quantum chemistry methods as an adequate methodology to understand these interactions.