I nervously click the “minimize” button and watch as the ligand shifts substantially in the active
site. Blue hydrogen bonds break and form in response to the ligand’s migration, as orange steric
clashes start to fade. When the ligand’s journey ends, I stare in disbelief: its affinity score is -13!
I cheer, but just as I begin to inform my teammates…
My alarm sounds, bringing me back to reality.
On Monday, just three days prior, we were introduced to the annual SSP Inhibitor Competition,
and the goal was simple: from our best (experimentally-determined) inhibitor, modify it to
increase its affinity with our enzyme. At first, I was indifferent. After all, how much control did we
really have over this inhibitor? Would simply adding a few functional groups be able to
substantially change our inhibitor’s affinity with our enzyme?
I quickly realized that I was wrong. With our six allotted additions, other teams were reaching
affinities of -12, -13, or even -15 kcal/mol, while most started with values around -6 kcal/mol.
With this unexpected and exciting amount of control, the inhibitor began to occupy more than
just our enzyme’s active site: it also seemed to have a high affinity with my mind. Before I knew
it, I had spent hours selecting and replacing key hydrogens with different functional groups, and
watching as our inhibitor evolved to fit the active site. By the end of Tuesday, I could see our
inhibitor when I closed my eyes. And, by the end of Wednesday, I was dreaming of reaching the
next affinity milestone.
Now, it is Saturday, and I worry what may happen next. In this brief period of lucidity, I have
written this blog; perhaps the last cohesive thing I will create during this program. The inhibitor
has entirely consumed me, and it seems likely that Sunday, our “free day” will be dedicated to
our inhibitor. It demands more time and energy, and its affinity with me is far too high to escape.
Be careful, and do not follow in my footsteps. Be wary of inhibitors.
-Jazzy
