There is a lovely story behind this paper just published earlier this week in Biochemistry. Reinhart Reithmeier came to visit Mark Sansom in Oxford whilst on sabbatical back in 2002. Now Reinhart, if you don’t know, is a world-expert on Band 3 which is the transmembrane protein in the membrane of red blood cells that mediates the exchange of bicarbonate ions (and hence, effectively, carbon dioxide). In particular he was interested in the effect that an inherited nine-residue deletion has on the first transmembrane helix (TM1). These deletion is known as South Asian Ovalocytosis (SAO) and has serious consequences for the individual but also offers some protection against the parasite that causes malaria.
Since there were some NMR structures of wild type and SAO TM1 available at the time, Reinhart persuaded a few people in Mark’s lab to run some simulations on a couple of the NMR structures from the NMR ensemble. In total 22 ns of molecular dynamics simulation was run, much of it in octane rather than a lipid bilayer. A manuscript was prepared and sent to the Biophysical Journal and the reviewers were interested but did not believe that the simulations were representative of the dynamics of TM1. Witness this comment
The 10 ns WT-NMR-PC simulation is unacceptable. This simulation has gone wrong as a consequence of poorly selecting their starting structure.
At the time this study was pushing the boundaries on how long transmembrane helices could be simulated before, yet this was not enough. Unfortunately by the time the comments were returned, the lead author had left the lab and science and so the project lost steam.
Let’s fast forward to 2013, eleven years later. Reinhart visits Mark’s lab again, clutching the original manuscript and reviewers’ comments. I get interested, partly through my earlier work on the roles proline residues can play in transmembrane proteins and decide that the only way to avoid another comment from a reviewer like the one above is to simulate ALL the structures in the NMR ensembles. Not only that, but let’s repeat each one three times and also try starting from an ideal helix as well (and repeat that fifty times).
Of course, this type of high-throughput simulation was now possible; computer speeds had increased, GPUs had been introduced and GROMACS continually optimised. We could now also use coarse-grained molecular dynamics simulations to embed each structure in a lipid bilayer and, just as importantly, run high-throughput analysis using MDAnalysis, a Python module able to read and analyse large numbers of molecular dynamics trajectories efficiently and quickly.
In total I ran 4,460 ns of molecular dynamics for this study, an increase of nearly 200x over the study a bit over a decade ago. Note that Moore’s Law alone is responsible for 50-150x so my main advantage was simply starting the simulations a decade later. This is a lovely illustration of how the gradual but relentless increases in computer speeds (along with other advances) have allowed us to push the boundaries of simulating the behaviour of biological molecules.