Variations in the Electrostatic Landscape of Class II Human Leukocyte Antigen Molecule Induced by Modifications in the Myelin Basic Protein Peptide: A Theoretical Approach

Abstract

The receptor-ligand interactions involved in the formation of the complex between Class II Major Histocompatibility Complex molecules and antigenic peptides, which are essential for establishing an adaptive immunological response, were analyzed in the Class II Human Leukocyte Antigen (HLA) - Myelin Basic Protein (MBP) peptide complex (HLA-DRβ1*1501-MBP) using a multipolar molecular electrostatic potential approach. The Human Leukocyte Antigen - peptide complex system was divided into four pockets together with their respective peptide fragment and the corresponding occupying amino acid was replaced by each of the remaining 19 amino acids. Partial atomic charges were calculated by a quantum chemistry approach at the Hatree Fock/3-21*G level, to study the behavior of monopole, dipole and quadrupole electrostatic multipolar moments. Two types of electrostatic behavior were distinguished in the pockets' amino acids: “anchoring” located in Pocket 1 and 4, and “recognition” located in Pocket 4 and 7. According to variations in the electrostatic landscape, pockets were ordered as: Pocket 1>Pocket 9≫Pocket 4≈Pocket 7 which is in agreement with the binding ability reported for Class II Major Histocompatibility Complex pockets. In the same way, amino acids occupying the polymorphic positions β13R, β26F, β28D, β9W, β74A, β47F and β57D were shown to be key for this Receptor-Ligand interaction. The results show that the multipolar molecular electrostatic potential approach is appropriate for characterizing receptor-ligand interactions in the MHC–antigenic peptide complex, which could have potential implications for synthetic vaccine design.

Structural and Dynamical Insights on HLA-DR2 Complexes That Confer Susceptibility to Multiple Sclerosis in Sardinia: A Molecular Dynamics Simulation Study

“…To further investigate the flexibility origin with respect to the five binding pockets (Fig. 3A) traditionally defined in the binding site [45], we divided the binding groove into four compartments (Fig. 3B), covering most of the peptide-binding pockets and analyzed the structural changes in each one, for the free and bound alleles (Fig.…”

“…Recent theoretical studies have used variations in the electrostatic landscapes of MHC class II binding groove to distinguish the pockets' amino acids with a specific anchoring (Pocket 1 and 4) or recognition (Pockets 4 and 7) property (Fig. 3A) [45]. Moreover, preferences in peptide-binding shown by different HLA-DRB1 allele variants, suggest also a relevant role of the residues surrounding the pockets in disease susceptibility [36].…”

HLA class II polymorphism in Latin American patients with multiple sclerosis

“…A multipolar molecular electrostatic potential analysis of the receptor-ligand interactions involved in the formation of the complex between HLA class II molecules and antigenic peptides (HLA-DRB1⁎ 1501-MBP) disclosed that amino acids occupying the polymorphic positions beta13R, beta26F, beta28D, beta9W, beta74A, beta47F and beta57D are relevant for this receptor-ligand interaction [35], which could have potential predictive and therapeutical implications.…”

Interaction between HLA-DRB1-DQB1 Haplotypes in Sardinian Multiple Sclerosis Population

“…Interestingly, Wucherpfennig and Strominger [24] suggested that MBP residues K93, F91, and H90 are primary TCR contact points. Therefore, we confirm that *14∶01 allele is showing a quite distinct capability to anchor the MBP peptide in pocket 4, with respect to *03∶01, particularly for residue K93, likely impacting on TCR recognition and ultimately in T cell triggering and activation.…”