The role of tryptophan side chains in membrane protein anchoring and hydrophobic mismatch

Abstract

Tryptophan (Trp) is abundant in membrane proteins, preferentially residing near the lipid-water interface where it is thought to play a significant anchoring role. Using a total of 3 μs of molecular dynamics simulations for a library of hydrophobic WALP-like peptides, a long poly-Leu α-helix, and the methyl-indole analog, we explore the thermodynamics of the Trp movement in membranes that governs the stability and orientation of transmembrane protein segments. We examine the dominant hydrogen-bonding interactions between the Trp and lipid carbonyl and phosphate moieties, cation-π interactions to lipid choline moieties, and elucidate the contributions to the thermodynamics that serve to localize the Trp, by ~4 kcal/mol, near the membrane glycerol backbone region. We show a striking similarity between the free energy to move an isolated Trp side chain to that found from a wide range of WALP peptides, suggesting that the location of this side chain is nearly independent of the host transmembrane segment. Our calculations provide quantitative measures that explain Trp's role as a modulator of responses to hydrophobic mismatch, providing a deeper understanding of how lipid composition may control a range of membrane active peptides and proteins.

Interaction of Human Chloride Intracellular Channel Protein 1 (CLIC1) with Lipid Bilayers: A Fluorescence Study

“…The relatively short distance measured from the FRET experiments of ~15 Å therefore indicates that the position for Trp35 is likely close to the lipid surface, conceivably assigning Trp35 as a key anchoring residue for membrane interaction. This location of Trp35 near the lipid surface is not entirely unexpected as tryptophan residues in membrane proteins usually reside near 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 the lipid-water interface 44 . It is the indole ring of the Trp side chain which has been identified to be responsible for anchoring and stabilizing several proteins to membrane, and may also assist proteins in partitioning and inserting into bilayers 45,46 …”

Structure-Activity Relationship of α Mating Pheromone from the Fungal Pathogen Fusarium oxysporum

“…Interestingly, the growth inhibitory activity was abolished in the D-Ala 1,2 and the scrambled analogs, both of which lack a tryptophan residue at the N or the C terminus, respectively. Aromatic residues, particularly tryptophan, have been reported to undergo specific interactions with lipid moieties resulting in anchoring to the membrane (37). The presence of the tryptophan residues Trp 1 and Trp 10 at the two termini suggests that they could act as a structural clamp during a potential membrane interaction linked to the growth inhibitory activity of the ␣-pheromone.…”

Interfacial Partitioning of a Loop Hinge Residue Contributes to Diacylglycerol Affinity of Conserved Region 1 Domains

“…solvent exclusion) will make a larger favorable contribution to the free energy of binding in wtC1B␦ compared with W252Y. The extended aromatic system of Trp, two fused rings, as opposed to one ring in Tyr, is likely to facilitate the cation-interactions (60) with positively charged choline groups of the lipids and detergents (61). Differences in the electric dipole moments of indole and phenol moieties (2.1 D and 1.2 D, respectively (56,62)) may contribute to the more favorable charge-dipole and dipole-dipole interactions of the Trp side chain with the complex electrostatic environment of the headgroup regions and the associated water.…”