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. 2013 Aug 6;105(3):648-56.
doi: 10.1016/j.bpj.2013.06.025.

Dodecyl maltoside protects membrane proteins in vacuo

Sarah L Rouse  1 , Julien Marcoux, Carol V Robinson, Mark S P Sansom
Affiliations

Dodecyl maltoside protects membrane proteins in vacuo

Sarah L Rouse et al. Biophys J. .

Abstract

Molecular dynamics simulations have been used to characterize the effects of transfer from aqueous solution to a vacuum to inform our understanding of mass spectrometry of membrane-protein-detergent complexes. We compared two membrane protein architectures (an α-helical bundle versus a β-barrel) and two different detergent types (phosphocholines versus an alkyl sugar) with respect to protein stability and detergent packing. The β-barrel membrane protein remained stable as a protein-detergent complex in vacuum. Zwitterionic detergents formed conformationally destabilizing interactions with an α-helical membrane protein after detergent micelle inversion driven by dehydration in vacuum. In contrast, a nonionic alkyl sugar detergent resisted micelle inversion, maintaining the solution-phase conformation of the protein. This helps to explain the relative stability of membrane proteins in the presence of alkyl sugar detergents such as dodecyl maltoside.

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Figures

Figure 1
Figure 1
Transfer of PDCs from water to vacuum using SMD simulations. (A) Three stages in the process are shown: 1), a PDC in water, with a water/vacuum interface; 2), application of an external force (red arrow with spring) to the center of mass of the PDC to pull it through the water/vacuum interface; leading to 3), the PDC in the vacuum phase with some water (cyan) remaining bound to the complex and the occasional water molecule (two small cyan spheres) escaping into the vacuum phase. (B) The arrangement of detergent molecules around BM2 in solution and after transfer to vacuum. The detergent tails are shown as a gray surface, the detergent headgroups are red, and the protein is yellow. Water is omitted for clarity.
Figure 2
Figure 2
Evaporation of water molecules from PDCs during extended simulations under dehydrating conditions in vacuo. (A) Snapshots from the final frames of each simulation show the protein in yellow cartoon representation and the detergent molecules as a surface with headgroups colored red and tails colored gray. Bound water molecules are shown as cyan spheres. (B) Hydrogen-bonding interactions of water molecules with detergent (black lines) and with protein (red lines) as functions of time.
Figure 3
Figure 3
Rearrangement of detergent molecules during simulation under dehydrating conditions. Radii of gyration for detergent headgroups (black trace) and tails (red trace) are shown, highlighting the micelle inversion of DHPC (A) and DPC (B), but not DDM (C). For BM2-DDM, radii are shown for the first (black trace) and second (blue trace) sugar ring of the DDM molecules. Isosurfaces correspond to the mean distribution (over the length of the simulation) of detergent headgroup (red) and tail (gray) atoms within 4 Å of the protein surface for each of the PDCs. In DHPC and DPC, there is partial exposure of the protein to vacuum, whereas in DDM the normal solution packing, in which the hydrophobic portion of the protein is covered by detergent tails, is maintained. The isosurfaces were generated using the VolMap plugin within VMD (51).
Figure 4
Figure 4
Area of BM2 protein unprotected by detergent molecules during simulations in vacuo. The traces show the hydrophobic surface area of BM2 exposed to vacuum (i.e., not in contact with detergent molecules) during simulation under dehydrating conditions. This surface area is lowest initially for DPC (red trace), but it increases rapidly as water is lost. By the end of the simulations the protein is most exposed in DPC (red trace), followed by DHPC (blue trace) then DDM (black trace).
Figure 5
Figure 5
Conformational changes of BM2 protein during simulations in vacuo. (A) Protein Cα atom RMSD as a function of time in DPC (red trace), DHPC (blue trace), and DDM (black trace). (B) Structures of the BM2 helix bundle at the start (cyan) and end (red) of the in vacuo simulations are superimposed. The greatest conformational changes are observed in the zwitterionic detergents DHPC and DPC, whereas the solution-phase conformation is largely maintained in DDM.
Figure 6
Figure 6
Destabilizing interactions of zwitterionic detergent molecules with BM2 protein during dehydration. (Upper) The change in conformation of the BM2-DDM complex at ∼0.62 μs (see Fig. 5) correlates with extraction of a water molecule (green and white) from the central pore, mediated by interactions with the headgroup of a DHPC molecule. The water and DHPC molecule are shown in spacefilling format, and the protein (yellow) in cartoon format. (Lower) Destabilizing interactions of DPC detergent molecules similar to those depicted above, with the C terminus of BM2 are observed, in which a single detergent molecule gradually becomes lodged between two of the transmembrane helices, interacting with water molecules and remaining within the pore for the duration of the simulation. Water molecules within 4 Å of this His27 residue are shown as a green surface.
Figure 7
Figure 7
The influence of dehydration on BM2 dynamics. Cα RMS fluctuations are shown at various stages of dehydration. For each PDC, Cα RMS fluctuations in the solution phase are shown in black, those for the first 50 ns in vacuo are in red, and those for 50–100 ns are blue. The loss of water correlates with a decrease in protein dynamics, with some decrease in the first 50 ns, and the dampening effect most pronounced for the 50–100 ns period, during which approximately half of the water molecules in the sparingly solvated complex have evaporated. The dynamics of the protein in DDM vary the least, with minimal difference between the solution phase and the beginning of the simulation under vacuum. The solution-phase protein dynamics are greater in the simulations with DHPC and DPC detergents than in those with DDM.
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