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3.4.3.3 Refinements of Ligand Backbone and Interacting Side Chain
To improve the accuracy of the initial model, partial refinement was performed for
both the ligand backbone and side chain, using ICM Biased Monte Carlo procedure
(Abagyan and Maxim 1999). Initial stages of refinements attempt to overcome the
penalty derived from the initial rigid docking of terminal residues by introducing
partial flexibility to the ligand backbone. Restraints were imposed upon the
positional variables of the Cα atoms of probes to keep it close to the starting
conformation. The energy function adopted for this refinement step is:
E
=
E
vw
+
E
hbonds
+
E
torsions
+
E
electr
+
E
solv
+
E
entropy
(3)
Refinements of ligand and receptor side-chain torsions in the vicinity of 4.00 Å
from the receptor were performed upon the final backbone structure.
3.5 Application of Docking Protocol
We will now illustrate the application of our protocol for the discrimination of
binders/nonbinders from MHC class II alleles. Concretely, we discuss the docking of
a 15-residue peptide ERVICPISSVPGNLA into the binding groove of associated and
nonassociated MHC class II alleles DRB1*0402 and DRB1*0406 respectively
(Tong, Bramson, Kanduc, Sinha, and Ranganathan 2006).
The core residues of each 15-residue peptide were generated using a sliding
window (size 9) to eliminate any bias in selecting core peptides based on sequence
patterns before the start of docking simulations. Docking of core peptide residues is
performed using the docking procedure earlier described followed by
ab initio
modeling of flanking residues. Our models present the best fit of each peptide into
the binding cleft of each disease-associated and non-disease-associated allele based
on the following criteria: (i) pattern of hydrogen bonding to the MHC molecule,
(ii) pattern of hydrophobic burial of peptide side chains, and (iii) the absence of atomic
clashes or repulsive contacts.
In this example, pMHC residues were considered to be in contact if at least one
pair of their nonhydrogen (“heavy”) atoms was found to be within 4.00-Å radius
(Fischer and Marquesee 2000). Intrapeptide interactions and intra-MHC interactions
were not considered as they have minor influence on backbone structure. Any atom
in the peptide and any atom in the MHC were considered to be experiencing atomic
clash if their separation is below 2.00 Å (Samudrala and Moult 1997) for non-
hydrogen atoms and below 1.60 Å for atoms participating in hydrogen bonds
(Samanta, Bahadur, and Chakrabarti 2002; Wallace, Laskowski, and Thornton
1995). Out of seven possible combinations of core peptide residues for the peptide,
only one conformation successfully docked into the binding cleft of DRB1*0402
without any atomic clashes or repulsive interactions. In contrast, atomic clashes are
experienced in nonassociated allele DRB1*0406 (Fig. 3).
