Biology Reference
In-Depth Information
populated by positively charged residues, with a total charge of
+
2
coming from two histidine residues and one arginine residue.
Based on the structural and functional characteristics of those
residues involved in the hydrophobic cluster, a base case was studied
with positions 1, 4, and 13 selected only from those residues defined as
belonging to the hydrophobic set (A,F,I,L,M,V,Y). In addition, this set
included threonine for position 13 to allow for the selection of the wild-
type residue at this position. For positions 9, 10, and 11 in the base case,
all residues were allowed, excluding cystine and tryptophan.
The sequence selection results exhibit several important and consis-
tent features. First, position 10 is dominated by the selection of a
histidine residue, a result that directly reinforces the composition of the
wild-type compstatin sequence. In contrast, position 11 is found to
have the largest variation in composition, with polar, hydrophobic, and
charged residues all being part of the set of optimal low-lying energy
sequences. At position 9, a subset of those residues chosen for position
11 is selected. When considering those positions involved in the
hydrophobic cluster of compstatin, it is evident that valine provides
strong forces at each position. However, the results for position 4 contrast
with those at positions 1 and 13 in that tyrosine, rather than valine, is
the preferred choice for the lowest as well as a large majority of the
low-lying energy sequences.
It should be noted that because the compstatin structure was deter-
mined via NMR methods, there exists an ensemble of 21 structures for
which alternative templates could be derived. These alternative tem-
plates were studied as a means of incorporating backbone flexibility
into the sequence selection process, and the results proved to be consis-
tent and in qualitative agreement with those for the average template
structure.
In view of the experimental studies on compstatin by Mallik et al. [81],
who proposed that tryptophan (W) or fused-ring nonnatural amino acids
at position 4 would contribute to high inhibitory activity of the peptide,
an additional run was performed with the inclusion of tryptophan (W)
in the selection set for position 4. Table 2.1 summarizes the preferred
selection at each position according to the composition of the lowest-
lying energy sequences. Tryptophan (W) was indeed strongly favored
at position 4, if it was included in the selection set. This observation
agrees with the experimental finding by Mallik et al. [81]. It should be
noted that if tryptophan (W) is allowed to be in the aforementioned
hydrophobic set for all six positions, then sequences with tryptophan
(W) in position 4, and alanine (A), phenyl (F), or tryptophan (W) in
position 9, are predicted among the most promising ones by the pro-
posed novel in silico sequence selection framework (position 1 is I,
position 10 is R, and position 13 is T, as in set D of figure 2.1).
Search WWH ::




Custom Search