Influence of glutamic acid residues and pH on the properties of transmembrane helices

Rajagopalan, Venkatesan; Greathouse, Denise V.; Koeppe, Roger E.

doi:10.1016/j.bbamem.2017.01.006

Cited by 13 publications

(27 citation statements)

References 39 publications

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“…At the next step of verification, we compared FMAP 2.0 predictions of TM and non-TM peptide arrangements in lipid bilayers with published experimental data. The test set 6 included synthetic pH-triggered membrane peptides with ionizable residues within hydrophobic α-helices studied by solid-state NMR, − ATR-FTIR spectroscopy, and OCD ,− at different pH values (50 data points for 32 peptides). These peptides were designed to examine the pH-dependent equilibrium between membrane-spanning TM α-helices and surface-bound non-TM states in model PC bilayers .…”

Section: Resultsmentioning

confidence: 99%

Thermodynamics-Based Molecular Modeling of α-Helices in Membranes and Micelles

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Schnitzer

Todd

et al. 2021

J. Chem. Inf. Model.

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The Folding of Membrane-Associated Peptides (FMAP) method was developed for modeling α-helix formation by linear peptides in micelles and lipid bilayers. FMAP 2.0 identifies locations of α-helices in the amino acid sequence, generates their three-dimensional models in planar bilayers or spherical micelles, and estimates their thermodynamic stabilities and tilt angles, depending on temperature and pH. The method was tested for 723 peptides (926 data points) experimentally studied in different environments and for 170 single-pass transmembrane (TM) proteins with available crystal structures. FMAP 2.0 detected more than 95% of experimentally observed α-helices with an average error in helix end determination of around 2, 3, 4, and 5 residues per helix for peptides in water, micelles, bilayers, and TM proteins, respectively. Helical and nonhelical residue states were predicted with an accuracy from 0.86 to 0.96, and the Matthews correlation coefficient was from 0.64 to 0.88 depending on the environment. Experimental micelle- and membrane-binding energies and tilt angles of peptides were reproduced with a root-mean-square deviation of around 2 kcal/mol and 7°, respectively. The TM and non-TM states of hydrophobic and pH-triggered α-helical peptides in various lipid bilayers were reproduced in more than 95% of cases. The FMAP 2.0 web server () is publicly available to explore the structural polymorphism of antimicrobial, cell-penetrating, fusion, and other membrane-binding peptides, which is important for understanding the mechanisms of their biological activities.

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Section: Resultsmentioning

confidence: 99%

Thermodynamics-Based Molecular Modeling of α-Helices in Membranes and Micelles

Lomize

Schnitzer

Todd

et al. 2021

J. Chem. Inf. Model.

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“…Our in silico calculations unveiled that the protonated state of D150, rather than the deprotonated state, stabilized the trimeric structure in the membrane bilayer. It should be noted that several studies have shown that the membrane environment can modulate the p K a values of charged residues dramatically to the direction of being neutral (p K a of 7) since the microenvironment (dielectric constant) is changed from the bulk solution to the hydrophobic membrane. − Therefore, it is not surprising that the measured p K a of D150 of TMD5 is 7.3–7.4, which is far from the p K a value (3.7) of Asp in water. Most likely the equilibrium shifts of D150 protonation states provide a mechanism for LMP-1 to manipulate its conformation and function in the different microenvironments of the host cell.…”

Section: Discussionmentioning

confidence: 97%

Dissecting Role of Charged Residue from Transmembrane Domain 5 of Latent Membrane Protein 1 via In Silico Simulations and Wet-Lab Experiments

et al. 2021

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Charged residues are frequently found in the transmembrane segments of membrane proteins, which reside in the hydrophobic bilayer environment. Charged residues are critical for the function of membrane protein. However, studies of their role in protein oligomerization are limited. By taking the fifth transmembrane domain (TMD5) of latent membrane protein 1 from the Epstein–Barr virus as a prototype model, in silico simulations and wet-lab experiments were performed to investigate how the charged states affect transmembrane domain oligomerization. Molecular dynamics (MD) simulations showed that the D150-protonated TMD5 trimer was stable, whereas unprotonated D150 created bends in the helices which distort the trimeric structure. D150 was mutated to asparagine to mimic the protonated D150 in TMD5, and the MD simulations of different D150N TMD5 trimers supported that the protonation state of D150 was critical for the trimerization of TMD5. In silico mutations found that D150N TMD5 preferred to interact with TMD5 to form the heterotrimer (1 D150N TMD5:2 protonated TMD5s) rather than the heterotrimer (2 D150N TMD5s:1 protonated TMD5). D150R TMD5 interacted with TMD5 to form the heterotrimer (1 D150R TMD5:2 protonated TMD5). These in silico results imply that D150N TMD5 and D150R TMD5 peptides may be probes for disrupting TMD5 trimerization, which was supported by the dominant-negative ToxR assay in bacterial membranes. In all, this study elucidates the role of charged residues at the membrane milieu in membrane protein oligomerization and provides insight into the development of oligomerization-regulating peptides for modulating transmembrane domain lateral interactions.

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“…20,31−33 While small changes in the local fraying are detected easily by the highly sensitive 2 H NMR methods, such changes involving helix terminal disorder may not necessarily be reflected in the circular dichroism spectra. 20,31 Notably, the helix disorder, whether arising from changes in end fraying or orientations of the core helix, is lipid-dependent as well as pH-dependent as the detailed behavior varies among bilayers of DLPC, DMPC, and DOPC. These features will be important for understanding the plasticity of protein functional domains for which, notably, the cholesterol content also is a significant regulatory factor.…”

Section: ■ Discussionmentioning

confidence: 99%

“…As a further background, E16 alone confers spectral broadening with little or no pH dependence for the core helix orientation yet significant local unwinding at high pH. 20 We now examine the influence of E16 upon the very stable Arg-anchored R14 helix, acetyl-GGALW 5 LALALALAR 14 ALALW 19 LAGA-amide, in bilayer membranes. Notably, the Glu residue is placed on the opposite face of the helix from that of the Arg residue, with 200°(or 360−200°) radial separation (Figure 1).…”

Section: ■ Introductionmentioning

confidence: 99%

Illuminating Disorder Induced by Glu in a Stable Arg-Anchored Transmembrane Helix

et al. 2021

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Membrane proteins are vital for biological function and are complex to study. Even in model peptide-lipid systems, the combined influence or interaction of pairs of chemical groups still is not well understood. Disordered proteins, whether in solution or near lipid membranes, are an emerging paradigm for the initiation and control of biological function. The disorder can involve molecular orientation as well as molecular folding. This paper reports an astonishing induction of disorder when one Glu residue is introduced into a highly stable 23-residue transmembrane helix. The parent helix is anchored by a single Arg residue, tilted at a well-defined angle with respect to the DOPC bilayer normal and undergoes rapid cone precession. When Glu is introduced two residues away from Arg, with 200° (or 160°) radial separation, the helix properties change radically to exhibit a multiplicity of three or more disordered states. The helix characteristics have been monitored by deuterium (2H) NMR spectroscopy as functions of the pH and lipid bilayer composition. The disordered multistate behavior of the (Glu, Arg)-containing helix varies with the lipid bilayer thickness and pH. The results highlight a fundamental induction of protein multistate properties by a single Glu residue in a lipid membrane environment.

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Influence of glutamic acid residues and pH on the properties of transmembrane helices

Cited by 13 publications

References 39 publications

Thermodynamics-Based Molecular Modeling of α-Helices in Membranes and Micelles

Thermodynamics-Based Molecular Modeling of α-Helices in Membranes and Micelles

Dissecting Role of Charged Residue from Transmembrane Domain 5 of Latent Membrane Protein 1 via In Silico Simulations and Wet-Lab Experiments

Illuminating Disorder Induced by Glu in a Stable Arg-Anchored Transmembrane Helix

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