Information Technology Reference
In-Depth Information
4.1 Introduction
Quantitative Structure-Activity Relationship (QSAR) analysis, as a predictive tool of
wide applicability, is one of the main cornerstones of modern cheminformatics and,
increasingly, bioinformatics. Immunoinformatics, a newly emergent subdiscipline of
bioinformatics, which addresses informatic problems within immunology, uses
QSAR technology to tackle the crucial issue of epitope prediction. As high-
throughput biology reveals the genomic sequences of pathogenic bacteria, viruses,
and parasites, such prediction will become increasingly important in the post-
genomic discovery of novel vaccines, reagents, and diagnostics. In order to better
understand the sequence dependence of peptide-MHC (Major Histocompatibility
Complex) binding of the mouse MHC, we have now used our approach to explore
the amino acid preferences of various human and mouse alleles.
The products of MHC play a fundamental role in regulating immune responses.
T cells recognize peptide fragments complexed with MHC molecules as antigens, a
process requiring antigen degradation through complex proteolytic digestion prior
to complexation. The biological role of MHC proteins is thus to bind peptides and
“present” these at the cell surface for inspection by T-cell antigen receptors
(TCRs). The MHC genes are grouped into two classes on the basis of their chemi-
cal structure and biological properties. The two types of MHC protein have related
secondary and tertiary structure but with important functional differences. Class I
molecules are composed of a heavy chain complexed to β2-microglobulin, while
class II molecules consist of two chains (α and β) of similar size. Both classes of
MHC molecule have similar 3D structures composed of two domains. The MHC
peptide-binding site consists of a β-sheet, forming the base, flanked by two
α-helices, which together form a narrow cleft or groove accommodating bound
peptides. The principal differences between the two classes are the dimensions of
the peptide-binding groove, which is constrained to bind 8- to 11-amino acid pep-
tides in class I, but is open at both ends in class II, allowing much larger peptides
of varying length to be bound.
Class II MHC molecules are non-covalently bonded heterodimers, called HLA-
DP, HLA-DQ, and HLA-DR in humans and I-A and I-E in mice. Peptides binding to
class II MHC molecules are usually 10-25 residues long, with lengths of 13-16
amino acids being the most frequently observed (Rudensky, Preston-Hurlburt, Hong,
Buus, and Tschinke 1991; Hunt, Michel, Dickinson, Shabanowitz, Cox, Sakaguchi,
and Appella 1992; Chicz, Urban, Lane, Gorga, Stern, Vignali, and Strominger 1992;
Chicz, Urban, Gorga, Vignali, Lane, and Strominger 1993). From X-ray crystallo-
graphic data of MHC class II and TCR-peptide-MHC class II complexes (Dessen,
Lawrence, Cupo, Zaller, and Wiley 1997; Hennecke and Wiley 2002), it is clear that
9 amino acids are bound in an extended conformation within the class II binding site.
They are not anchored at their amino and carboxyl termini, but stretch along the
binding groove, with residues accommodated by binding pockets along the cleft.
Previous interpretations, reported in the literature, suggest that class II peptides have
a small number of anchor residues upon which binding depends. These anchors are
residues of an appropriate type, which must sit at particular spacings along the pep-
tide in order for allele-restricted binding to occur; residues at other peptide positions
