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Residue-specific side-chain packing determines the backbone dynamics of transmembrane model helices.


ABSTRACT: The transmembrane domains (TMDs) of membrane-fusogenic proteins contain an overabundance of ?-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 ?-helix force both ?-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.

SUBMITTER: Quint S 

PROVIDER: S-EPMC2955363 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Residue-specific side-chain packing determines the backbone dynamics of transmembrane model helices.

Quint Stefan S   Widmaier Simon S   Minde David D   Minde David D   Hornburg Daniel D   Langosch Dieter D   Scharnagl Christina C  

Biophysical journal 20101001 8


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 molec  ...[more]

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