Residue-specific side-chain packing determines the backbone dynamics of transmembrane model helices.
The transmembrane domains (TMDs) of membrane-fusogenic proteins contain an overabundance of β-branched residues. In a previous effort to systematically study the relation among valine content, fusogenicity, and helix dynamics, we developed model TMDs that we termed LV-peptides. The content and position of valine in LV-peptides determine their fusogenicity and backbone dynamics, as shown experimentally. Here, we analyze their conformational dynamics and the underlying molecular forces using molecular-dynamics simulations. Our study reveals that backbone dynamics is correlated with the efficiency of side-chain to side-chain van der Waals packing between consecutive turns of the helix. Leu side chains rapidly interconvert between two rotameric states, thus favoring contacts to its i±3 and i±4 neighbors. Stereochemical restraints acting on valine side chains in the α-helix force both β-substituents into an orientation where i,i±3 interactions are less favorable than i,i±4 interactions, thus inducing a local packing deficiency at VV3 motifs. We provide a quantitative molecular model to explain the relationship among chain connectivity, side-chain mobility, and backbone flexibility. We expect that this mechanism also defines the backbone flexibility of natural TMDs.
Quint
Stefan
S
Technische Universität München, Freising, Germany.
Widmaier
Simon
S
Minde
David
D
Hornburg
Daniel
D
Langosch
Dieter
D
Scharnagl
Christina
C
D000577:Amides / Q000737:chemistry; D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000737:chemistry*; D006860:Hydrogen Bonding; D007536:Isomerism; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D015203:Reproducibility of Results; D012997:Solvents / Q000737:chemistry; D014270:Trifluoroethanol / Q000737:chemistry; D014867:Water / Q000737:chemistry
D000577:Amides; D010455:Peptides; D012997:Solvents; D014867:Water; D014270:Trifluoroethanol