I can’t live without my radio…frequency pulse

I was looking through recent literature this past week and found a few things in JACS that I thought were particularly interesting.

The first comes from Kelly Damm and Heather Carlson, and substantiates my feeling that NMR is the coolest technique ever invented. In this case, they were trying to figure out the best way to incorporate protein flexibility into structure-based drug design. The authors previously established an MD method to generate multiple protein conformations of a single protein; the resultant ensemble worked better in assigning known inhibitors or non-inhibitors appropriately than a static structure. But all those calculations take a lot of time, and so Damm and Carlson went to the pdb, pulling out 90 static structures of HIV-1 protease (bound to a variety of ligands) and one NMR structure, which is actually an ensemble of 28 structures. What they discovered is that the success of these two ensembles was quite similar in identifying inhibitors, but that the NMR structure was less specific to a given ligand and so was more able to identify the essential features of the ligand and extrapolate to new classes of compounds. So, they suggest NMR structures as useful tools for SBDD. Go NMR!

Two communications also caught my eye: one, from Scott Miller’s group, extends his work on small, peptide-based catalysts to an Asp-catalyzed asymmetric epoxidation. In this case, putting the Asp carboxylate into a protected tripeptide known to form beta-turns resulted in a catalyst that could turn over nearly 20 times, with 97% yield and 92% ee in optimized conditions. He wrote a nice review on the rationale for this work now three years ago, but I would still recommend it. The second is work from John Klassen’s lab: Amidst the ongoing controversy of what gas-phase analysis of proteins really means, they seem to have put together a nice method for monitoring ligand binding sites, and determining whether the sites are identical (linear slope of ligand released over time and temperature) or not (non-linear slope).

Well, that’s my weekend reading. Now back to watching Wimbledon…

(ed’s note: Dr. Carlson alerted me to the fact that the study was actually about HIV protease, which I fixed 07/05)

Catherine (associate editor, Nature Chemical Biology)