Quantum Chemical Analysis of MHC-Peptide Interactions for Vaccine Design

Abstract

The development of an adequate immune response against pathogens is mediated by molecular interactions between different cell types. Among them, binding of antigenic peptides to the Major Histocompatibility Complex (MHC) molecule expressed on the membrane of antigen presenting cells (APCs), and their subsequent recognition by the T cell receptor have been demonstrated to be crucial for developing an adequate immune response. The present review compiles computational quantum chemistry studies about the electrostatic potential variations induced on the MHC binding region by peptide’s amino acids, carried out with the aim of describing MHC–peptide binding interactions. The global idea is that the electrostatic potential can be represented in terms of a series expansion (charge, dipole, quadrupole, hexadecapole, etc.) whose three first terms provide a good local approximation to the molecular electrostatic ‘landscape’ and to the variations induced on such landscape by targeted modifications on the residues of the antigenic peptide. Studies carried out in four MHC class II human allele molecules, which are the most representative alleles of their corresponding haplotypes, showed that each of these molecules have conserved as well as specific electrostatic characteristics, which can be correlated at a good extent with the peptide binding profiles reported experimentally for these molecules. The information provided by such characteristics would help increase our knowledge about antigen binding and presentation, and could ultimately contribute to developing a logical and rational methodology for designing chemically synthesized, multi-antigenic, subunit-based vaccines, through the application of quantum chemistry methods.

Signal peptides and trans-membrane regions are broadly immunogenic and have high CD8+ T cell epitope densities: Implications for vaccine development

“…An alternative to whole-pathogen based vaccines are subunit peptide vaccines (Brossart et al, 2000). These vaccines are composed of small peptides presented to T lymphocytes in the context of MHC molecule (Agudelo and Patarroyo, 2010). These peptides are fully synthetic, non-hazardous and usually easy to maintain in ambient conditions, enabling the vaccination of populations in countries with lower medical standards.…”

PREDIVAC: CD4+ T-cell epitope prediction for vaccine design that covers 95% of HLA class II DR protein diversity

“…Fifteen contacting positions on the polymorphic β-domain were finally considered as SDRs, providing they exerted an influence on peptide binding, they were structurally conserved, they were polymorphic and they were identified previously [34] to have an influence on the electrostatic properties of the binding groove (Additional file 1: Figure S1). These key positions allow the relative weight of the effect of all amino acids on each binding site to be determined, and predicting whether a peptide is a likely ligand for a given HLA class II protein.…”

“…Sequence variability of HLA molecules at the binding interface was mapped onto the DRB1*0101 allele structure [PDB:1A6A] using the Protein Variability Server (PVS) [33]. SDR identification was also aided by a previous quantum chemistry-based analysis of peptide:HLA class II interaction [34], where the variation of electrostatic properties associated with each of the residues involved in peptide binding was assessed and amino acids inducing a global variation of electrostatic properties in the binding groove (anchoring amino acids) and those involved in specific electrostatic variations (recognition amino acids, responsible for a differential effect) were identified.…”

Relationship between HLA-DRB1 Allele Polymorphisms and Familial Aggregations of Hepatocellular Carcinoma

“…Class ii hlas-named hla-d and subclassified into hla-dr, hla-dq, hla-dp, and so on-are expressed mainly in immunocells. They function as labelled molecules to activate the immune response and regulate the interaction of immunocells [22][23][24] .…”