Atomistic mechanism of transmembrane helix association

Abstract

Transmembrane helix association is a fundamental step in the folding of helical membrane proteins. The prototypical example of this association is formation of the glycophorin dimer. While its structure and stability have been well-characterized experimentally, the detailed assembly mechanism is harder to obtain. Here, we use all-atom simulations within phospholipid membrane to study glycophorin association. We find that initial association results in the formation of a non-native intermediate, separated by a significant free energy barrier from the dimer with a native binding interface. We have used transition-path sampling to determine the association mechanism. We find that the mechanism of the initial bimolecular association to form the intermediate state can be mediated by many possible contacts, but seems to be particularly favoured by formation of non-native contacts between the C-termini of the two helices. On the other hand, the contacts which are key to determining progression from the intermediate to the native state are those which define the native binding interface, reminiscent of the role played by native contacts in determining folding of globular proteins. As a check on the simulations, we have computed association and dissociation rates from the transition-path sampling. We obtain results in reasonable accord with available experimental data, after correcting for differences in native state stability. Our results yield an atomistic description of the mechanism for a simple prototype of helical membrane protein folding.

Lipid-mediated Association of the Slg1 Transmembrane Domains in Yeast Plasma Membranes

“…In the pre-dimerized state, the two TMDs are only weakly coupled and represent a LH configuration, which agrees with the observations in refs. 13,16,61 In contrast, the free energies of dimerization and the structure of the dimer depend on the lipid composition. Concerning the free energies, this dependence can be rationalized via some general characteristics.…”

The guidance and adhesion protein FLRT2 dimerizesin cisvia dual Small-X3-Small transmembrane motifs

“…Our models revealed a dynamical equilibrium between conformations involving two successive Small-X 3 -Small motifs: G 544 -X 3 -G 548 and G 545 -X 3 -G 549 motifs. To further assess these models and the conformational changes governing the FLRT2 dimer association, one could use accelerated MD simulations combined with free energy calculations 69,70 . To enable this, we are releasing the three main conformations (RH1, RH2 and LH) both in coarse The interconversion in between RH1, involving the G 545 -G 549 motif (in red), and RH2 interactions, driven by the A 544 -G 548 motif (in green), may be modulated by mutations in the TM domain or environmental conditions such as changes in the lipid composition of the membrane.…”

“…Our models revealed a dynamical equilibrium between conformations involving two successive Small-X 3 -Small motifs: G 544 -X 3 -G 548 and G 545 -X 3 -G 549 motifs. To further assess these models and the conformational changes governing the FLRT2 dimer association, one could use accelerated MD simulations combined with free energy calculations 69,70 . To enable this, we are releasing the three main conformations (RH1, RH2 and LH) both in coarse grained and atomistic representations ( https://github.com/MChavent/FLRT ).…”

Transition Path Sampling as Markov Chain Monte Carlo of Trajectories: Recent Algorithms, Software, Applications, and Future Outlook

“…Related to enzymes are molecular configurational changes in proteins, [60,62,[132][133][134] (including protein dissociation [68] ), lipids, [135] DNA, [136][137][138][139][140][141] and even transport across ion channels. [142] Here, the challenge is that paths tend to be more diffusive, and thus longer (order 1-10 ns), and states are more difficult to define.…”