Molecular Dynamics Simulations of Model Trans-Membrane Peptides in Lipid Bilayers: A Systematic Investigation of Hydrophobic Mismatch

Abstract

Hydrophobic mismatch, which is the difference between the hydrophobic length of trans-membrane segments of a protein and the hydrophobic width of the surrounding lipid bilayer, is known to play a role in membrane protein function. We have performed molecular dynamics simulations of trans-membrane KALP peptides (sequence: GKK(LA)nLKKA) in phospholipid bilayers to investigate hydrophobic mismatch alleviation mechanisms. By varying systematically the length of the peptide (KALP15, KALP19, KALP23, KALP27, and KALP31) and the lipid hydrophobic length (DLPC, DMPC, and DPPC), a wide range of mismatch conditions were studied. Simulations of durations of 50-200 ns show that under positive mismatch, the system alleviates the mismatch predominantly by tilting the peptide and to a smaller extent by increased lipid ordering in the immediate vicinity of the peptide. Under negative mismatch, alleviation takes place by a combination of local bilayer bending and the snorkeling of the lysine residues of the peptide. Simulations performed at a higher peptide/lipid molar ratio (1:25) reveal slower dynamics of both the peptide and lipid relative to those at a lower peptide/lipid ratio (1:128). The lysine residues have favorable interactions with specific oxygen atoms of the phospholipid headgroups, indicating the preferred localization of these residues at the lipid/water interface.

Lipid mediated packing of transmembrane helices – a dissipative particle dynamics study

“…This increase matches with the previously reported results 14,16 and displays a slope similar to the one observed in natural helices. 26 In super-positive mismatched helices (Dd T 20Å) we observe a change in the slope of tilt angle, as helices tend to adopt a higher tilt angle.…”

“…This effect was previously observed for synthetic peptides, 14,16,19 though it differs signi-cantly from what is observed in natural helices. 26 In synthetic helices, as well as in our current model, the ends of the helix are hydrophilic and so are forced to be in contact with the hydrophilic part of the membrane (or water).…”

Tryptophan-scanning Mutagenesis in the αM3 Transmembrane Domain of the Muscle-type Acetylcholine Receptor

“…First, in the positive hydrophobic mismatch condition, i.e. a protein hydrophobic length that is greater than the thickness of the lipid hydrophobic region, simulated of transmembrane peptides in lipid bilayers, can adopt various tilt angles to reduce the exposure to polar environment (81). Second, the highest number of incorporation sites by a photoactivable hydrophobic probe, 3-trifluoromethyl-3-(m-[ 125 I]iodophenyl)diazirine, into the lipid-exposed domains of the AChR in the absence of carbamylcholine (agonist analogue) indicates that the surface of the lipid-AChR interface in the resting state is larger than in the desensitized state (12).…”

Folding and insertion thermodynamics of the transmembrane WALP peptide

“…17,18 For instance, a positive mismatch leads to an average tilt angle between the peptide and the membrane normal, a quantity that can be determined from both experiments (e.g., quadrupolar splittings from 2 H solid-state NMR 19 ) and computer simulations. [20][21][22] Notably, Monticelli et al resolved an apparent discrepancy between the average tilt angle extracted from experiment versus the same observable calculated in molecular dynamics simulations. Using a coarsegrained (CG) model, and hence being able to access much longer time scales, they showed that both experiment and simulation agree, thus highlighting the importance of sampling the tilt angle over the microsecond time scales relevant for NMR experiments.…”