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Figure 4. Schematic representation of the second-
ary structure of the monomer of WT-TTR. The
spheres indicate the positions of the Cα atoms of
19 out of a total of 52 hydrophobic residues, co-
occurring in three of the association rules sets.
The four hydrophobic residues identified occur
as consequents of the association rules obtained
from the WT-TTR unfolding simulations.
Insights on the Stability of the
Hydrophobic Core of Transthyretin
We define the hydrophobic core of the protein as the
group of hydrophobic residues which in the protein
native structure have solvent accessible surface
area values lower or equal to 25%. According to
this definition, the hydrophobic core of WT-TTR
is composed of 29 amino-acid residues.
In the five sets of association rules derived from
the SASA variation profiles of the hydrophobic
residues, a total of 33 residues are identified, of
which 19 residues are present in all sets of associa-
tion rules. Figure 4 shows the distribution of these
residues in the native structure of WT-TTR, and
it is clear that all the residues are closely packed
in the interior of the protein monomer. We have
previously proposed that this group of amino-acid
residues may constitute the hydrophobic clusters
essential to the protein folding and unfolding
processes (Azevedo, 2005). In fact, we found
that all the 19 amino-acid residues conserved in
the five sets of association rules belong to the
hydrophobic core of WT-TTR. Moreover, most
of these residues participate in the formation of
β-strands (84.2% in β-strands, 5.3% in α-helix,
10.5% in turns and loops), which are well defined
topologies that contribute to the structural stabil-
ity of proteins.
There are 98 rules co-occurring exactly
in three sets of association rules. These rules
involve exactly four residues, and the average
support value is 46.4%. There are 21 hydro-
phobic residues involved in the rules identi-
fied, all of which belong to the hydrophobic
core of the protein. Moreover, these residues
are mainly located in β-strands A, B, E, F and
G. In Table 3, we show a selection of seven
rules in the conditions described. For example,
association rule AR1, states that, in Runs 1, 3
and 4, the set of residues Leu12, Ala25, Ile73
and Phe95 exhibit SASA values ≤ 25% dur-
ing approximately 31%, 47% and 51% of the
simulated time, respectively. Moreover, when
residues Ala25, Ile73 and Phe95 exhibit SASA
values ≤ 25%, then at least in ~ 93% of the cases
Leu12 also exhibits SASA values ≤ 25%. The
other association rules in Table 3 can be read
in a similar manner.
Comparison of the Sets of
Association Rules
The number of association rules extracted from
each data set varies considerably (Table 2). We
compared the sets of association rules derived from
the five data sets on the SASA variation profiles
of the individual amino-acid residues of WT-TTR
monomer. We found that an association rule co-
occurs in a maximum of three out of the five sets of
rules. Then, we investigated in more detail, the set
of association rules resulting from this comparison
as these rules may describe significant events in
the unfolding process of WT-TTR.
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