Valine-Induced Packing Deficiencies of Transmembrane Domains Promote Helix Flexibility and Membrane Fusion

Abstract

The helical transmembrane domains of fusion proteins are known to be functionally important and display an overabundance of helix-destabilizing Ile and Val residues. In an effort to systematically study the relationship of helix flexibility and fusogenicity, synthetic LV-peptides were designed whose hydrophobic core consists of Leu and Val residues at different ratios and at different positions (Hofmann et al., 2004; Poschner et al., 2009). The ability of the LV-peptides to fuse membranes increases with the content of helix-destabilizing residues. Molecular dynamics simulations were performed in order to characterize the backbone dynamics of these peptides in membrane-mimicking 80% TFE solvent and to relate the hydrogen-bond dynamics to experimental deuterium/hydrogen exchange kinetics. The analysis revealed that (i) the backbone dynamics of the helices increases systematically with Val content, (ii) that the impact of Val is due to stereochemical constraints within the helical structure and (iii) that side-chain packing mainly determines exchange kinetics. As a consequence, VxxV and VVxVV motifs promote helix destabilization whose relevance for membrane fusogenicity will be discussed.Hofmann, M.W., K. Weise, J. Ollesch, A. Agrawal, H. Stalz, W. Stelzer, F. Hulsbergen, H. deGroot, K. Gerwert, J. Reed, and D. Langosch. 2004. De novo design of conformationally flexible transmembrane peptides driving membrane fusion. Proc. Natl. Acad. Sci. U S A 101:14776-14781.Poschner, B.C., S. Quint, M. Hofmann, and D. Langosch. 2009. Sequence-specific conformational dynamics of model transmembrane domains determines their membrane fusogenic function. J. Mol. Biol. 386:733-741.