TY - JOUR
T1 - Residue-specific side-chain packing determines the backbone dynamics of transmembrane model helices
AU - Quint, Stefan
AU - Widmaier, Simon
AU - Minde, David
AU - Hornburg, Daniel
AU - Langosch, Dieter
AU - Scharnagl, Christina
N1 - Funding Information:
This work was supported by the State of Bavaria, the Center of Integrated Protein Science Munich, and the Deutsche Forschungsgesellschaft (DFG Project SFB 533/B2). Computer resources were provided by the Leibniz Rechenzentrum der Bayerischen Akademie der Wissenschaften.
PY - 2010/10/20
Y1 - 2010/10/20
N2 - The transmembrane domains (TMDs) of membrane-fusogenic proteins contain an overabundance of b-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.
AB - The transmembrane domains (TMDs) of membrane-fusogenic proteins contain an overabundance of b-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.
UR - http://www.scopus.com/inward/record.url?scp=78049336297&partnerID=8YFLogxK
U2 - 10.1016/j.bpj.2010.08.031
DO - 10.1016/j.bpj.2010.08.031
M3 - Article
AN - SCOPUS:78049336297
SN - 0006-3495
VL - 99
SP - 2541
EP - 2549
JO - Biophysical Journal
JF - Biophysical Journal
IS - 8
ER -