TGQR 2010Q2 Report.pdf - Teragridforum.org

Figure 2-3. Illustration of the three main flap conformations of HIV-1 Protease, from left to right, closed, semi-open, wideopen.
Western Europe. Subtype C is found in East and Southern Africa and throughout Eastern Asia.
Subtype F is predominantly found in South America.
The HIV protease has become an attractive target for drug design due to its role of cleaving the
gag and gag-pol polyprotein precursors. Furthermore, inhibition of the protease’s natural
biological function would prevent the maturation of the HIV, hence preventing the infection of
neighboring cells. The flap domain is the most mobile of all domains, largely attributed to the
number of Gly residues found in this region. Due to the importance of the flaps having to open
and close in order for catalytic activity to occur, it has been suggested by previous works that the
development of a new class of protease inhibitors that instead target the flap domain or other
essential domains might be more effective than the original idea of developing a protease
inhibitor that works through competitive inhibition. In this current study, Roitberg and his
students investigate conformational dynamics of the flaps, and the size of active site in order to
correlate how the different sequences of subtypes A, B, C and F allow for different conformations
of the protease.
The Molecular Dynamics simulations were performed on Kraken using a version of the AMBER
software optimized specifically for this problem as part of a TeraGrid Advanced User Support
project between Prof. Roitberg and
SDSC. Each of the simulations was run
for 220 ns in which between 204 and 256
processors were used for each
independent run.
The results indicate that the different
subtypes have different mobilities,
particular in the protein flaps, which in
term affect substrate and inhibitor access
to the active site. Given these differences,
one can rationalize for instance that
certain inhibitors, designed to work
against subtype B of HIV Protease (the
subtype prevalent in Europe and North
America) do not bind as well to subtype
A and C (prevalent in Africa and
responsible for 60% of the overall HIV
infections). Using this information, we
will work on designing inhibitors better
tailored to the less studied subtypes.
Figure 2-4. Snapshots from the simulation of subtype C
superimposed, which illustrate the mobility of the flaps.
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