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and for a strong hydrophobic residue Val (H2-K
b
) and Ile, Val, and Phe (H2-K
k
) at
position 8, which is in accordance with the studies of Falk (Falk, Rötzschke,
Stevanovic, Jung, and Rammensee 1991). It is found that in H2-K
b
the B pocket is
large enough to accommodate a bulky Ile residue at position 2, which is in accor-
dance with the crystal structure of the antigenic peptide from the ovalbumin complex
OVA-8 (SIINFEKL). In H2-K
b
and H2-K
k
alleles, the results showed that Tyr, Phe,
and Leu are all favored in position 3 (Fremont et al. 1992), which is situated in part
of pocket D and would significantly deepen the depth and volume of the D pocket
and is complementary to the pocket. The anchor carboxyl-terminal (position 8) pre-
fers hydrophobic residues, which fall into pocket F. Such results show that the pep-
tide binding cleft is closed at both ends, that the cleft has the same length in all class
I molecules, that the carboxyl-terminal peptide position is deeply buried in the F
pocket, and that there is little restriction on amino acids bound by pocket A
(Doytchinova et al. 2002c; Doytchinova and Flower
2003;
Guan et al. 2003a;
Hattotuwagama et al. 2004; Saper et al. 1991).
Our study has identified favored and
disfavored regions which are consistent with both the properties of peptide positions
and those of pockets, designated by A to F, within the MHC binding groove. It is
well known that each class I mouse MHC allele binds a mixture of structurally di-
verse peptides, typically 8-10 amino acids in length, and that each allele possesses
defined peptide specificity. The crystal structure of several mouse class I molecules
(Fremont et al. 1995; Zhang et al. 1992; Young et al. 1994; Smith et al. 1996a; Smith
et al. 1996b)
has helped to rationalize observed peptide binding.
4.4.2 Comparative Molecular Similarity Index Analysis (CoMSIA)
The motif of HLA-A3 superfamily includes main anchor positions 2 and 9 (Zhang,
Gavioli, Klein, and Masucci 1993).
Peptides bound to members of the A3 family
usually had a positively charged residue—arginine or lysine—at the C-terminus, and
a variety of hydrophobic residues at position 2. It was found that steric bulk was
favored at position 2 for A*0301 and A*3101 but disfavored in A*1101 and A*6801
models. The study of crystal structures of MHC molecules showed that the residue at
peptide position 2 bound in pocket B (Saper et al. 1991; Madden, Gorga, Strominger,
and Wiley 1991).
There are different residues lining pocket B in the different MHC-
A3 molecules: Tyr9 in A*1101 and A*6801, Phe9 in A*0301, and Thr9 A*3101
(Schönbach, Koh, Sheng, Wong, and Brusic 2000).
This means more space in pocket
B for A*0301 and A*3101, allowing them to accommodate larger side chains. Elec-
trostatic potential, hydrophobicity, and hydrogen bond acceptance maps were very
varied at this position. This was in good agreement with the broad spectrum of amino
acids observed at this position, from the bulky hydrophobic Leu to the small polar
Thr. The most important property for the amino acid at position 9 was hydrogen-
bond donor ability. It was favored by A*6801 and A*3101, and was disfavoured by
A*1101. For A*0301 were found areas of favored and disfavored hydrogen bond
donor groups at this position. In some cases, the change of Lys to the larger residue
Arg could affect the expression of the molecule (Zhang et al. 1993).
Results from the
present study suggested the interaction between the residue at peptide position 9 and
the MHC molecule may play an important role. The side chain of larger basic residue
