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. 2010 Oct 20;99(8):2541-9.
doi: 10.1016/j.bpj.2010.08.031.

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

Stefan Quint  1 , Simon Widmaier, David Minde, Daniel Hornburg, Dieter Langosch, Christina Scharnagl
Affiliations

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

Stefan Quint et al. Biophys J. .

Abstract

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.

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Figures

Figure 1
Figure 1
Sequence- and residue-specific structural and dynamical variations of LV-peptides of type A. The results for the B-peptides are shown in Fig. S5. Error bars indicate standard errors calculated from 10 ns block averages. Val positions are shaded in gray. (A) Cα-RMSD from an ideal α-helix. Overall rotations and translations were eliminated by a rigid-body fit to the reference structure. (B) Population of α-helical and 310-helical H-bonds. In <5% of the trajectories, the amide protons form bifurcated H-bonds.
Figure 2
Figure 2
Graphical representation of LV-peptide dynamics. For each peptide 20 exemplary structures taken every 5 ns are superimposed. The Cα atoms of residues 5–20 are oriented with a rigid body to an ideal α-helix shown in black. The color code indicates the average population of α-helical H-bonds (compare Fig. 1B and Fig. S5B). For peptides in the upper row (class A) the content of Val increases from left to right. Peptides in the lower row (class B) maintain the Leu/Val ratio of the parental LLV16, but Val is concentrated at peripheral or central parts of the sequence. The sequences are given in Table 1.
Figure 3
Figure 3
Sequence- and residue-specific side-chain packing of LV-peptides of type A. Val positions are shaded in gray. The results for the B-peptides are shown in Fig. S6. (A) Contact densities nP defined by the number of noncovalent heavy peptide atoms in a spherical region with radius 7 Å around the amide protons. The solvent coordination numbers in the same volume are given in Fig. S7. (B) VDW interaction Wsc-sc between the side chain as position i and all other side chains. The side-chain to backbone VDW interactions are shown in Fig. S8.
Figure 4
Figure 4
Side-chain rotamers and VDW contacts. (A and B) Exemplary contacts for Leu and Val side chains. (A) Val at position 12 in VVL16 populates mainly the trans rotamer (∼85%). (B) Leu at position 13 in LV16 swaps between tg+ (∼60%, left panel) and g−t (∼40%, right panel). Frames were taken every 20 ps and oriented with a rigid-body fit to optimize overlay of the N-Cα-C plane of the residue with an ideal α-helix (drawn as ribbon). Positions of the methyl carbons are drawn as dark (Cδ1 and Cγ1) and light-colored (Cδ2 and Cγ2) dots distributed around their ideal positions (larger white spheres). Side-chain contacts within 5 Å to methyl carbons at spacing i±3 and i±4 are labeled by the residue types involved. XYk denotes the interaction of residue X at position i with residue Y at position i+k. (C) VDW interactions of side-chain pairs in aliphatic A-peptides at different spacing. Upper panel: Averages from the MD trajectories (black) are compared with those calculated for an ideal α-helix (gray) using the rotamer populations observed in the simulations. Error bars indicate standard deviations as a result of the spread of the data for different peptides and the fluctuations within one trajectory. Lower panel: The dependence of pairwise interaction energies on Leu rotamer orientations is symbolized by arrows (↑ = g−t; ↓ = tg+). For LLk pairs, the upper arrow indicates the orientation of Leu at position i. The less favorable side-chain to backbone interaction of g−t as compared to tg+ disfavors the simultaneous population of g−t at positions i and i+k. For Val, only results for the trans rotamer are included.
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