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The centriolar protein CPAP G-box: an amyloid fibril in a single domain.

Cutts EE, Inglis A, Stansfeld PJ, Vakonakis I, Hatzopoulos GN - Biochem. Soc. Trans. (2015)

Bottom Line: Molecular dynamics simulations support the stability of the G-box domain even in the face of truncations or amino acid substitutions.G-box fibrils were observed in crystals as well as in solution and are also supported by simulations.We conclude that the G-box domain may well represent the best analogue currently available for studies of exposed β-sheets, unencumbered by additional structural elements or severe aggregations problems.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University of Oxford, Oxford, OX1 3QU, U.K.

No MeSH data available.


Related in: MedlinePlus

Analysis of the G-box structure throughout 100 ns of atomistic MD simulations(A) Secondary structure composition as function of amino acid residue and simulation time and (B) inter-strand twist angle as function of simulation time. The specific strand pairs are indicated. (C) One MD simulation of an I1067G substitution on β-strand 13 yielded large fluctuations in twist and eventually in breakage of the β-sheet. Shown here are (top) a snapshot of the G-box model at the end of this MD simulation and (bottom) inter-strand twist angles for the region surrounding the I1067G substitution.
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Figure 2: Analysis of the G-box structure throughout 100 ns of atomistic MD simulations(A) Secondary structure composition as function of amino acid residue and simulation time and (B) inter-strand twist angle as function of simulation time. The specific strand pairs are indicated. (C) One MD simulation of an I1067G substitution on β-strand 13 yielded large fluctuations in twist and eventually in breakage of the β-sheet. Shown here are (top) a snapshot of the G-box model at the end of this MD simulation and (bottom) inter-strand twist angles for the region surrounding the I1067G substitution.

Mentions: In order to further investigate the unique nature of this domain, we used atomistic MD simulations to gain insight in the stability and flexibility of the structure. Starting from the crystallographic model 4LD1 we performed 100 ns-long simulations [5], throughout which the G-box structure remains stable as it retains the main chain hydrogen bonding network and secondary structure elements (Figure 2A; Supplementary Table S1; Supplementary Movie S1). Minimal distortions are visible in the terminal β-strands where the protein N- and C-termini tend to fold back and interact with the β-sheet; these distortions are transient and manifest as slightly higher than average inter-strand twist angles at the terminal β-strands (Figure 2B). The overall G-box β-sheet twist remains left-handed throughout the MD simulations although it flattens somewhat to 130±30° from the 168° starting point. In addition, an average length of seven amino acids is maintained for the majority of β-strands throughout the simulations (Figure 2A). Hence, the G-box structure retains an energetically favourable conformation with respect to its twist [30] and typical strand length [31]. Further domain motions in the MD simulations result in slight β-sheet bending, such that the average end-to-end distance is 72 Å compared with 75 Å in the starting model and transient fanning of β-strand termini as single hydrogen bonds break and reform.


The centriolar protein CPAP G-box: an amyloid fibril in a single domain.

Cutts EE, Inglis A, Stansfeld PJ, Vakonakis I, Hatzopoulos GN - Biochem. Soc. Trans. (2015)

Analysis of the G-box structure throughout 100 ns of atomistic MD simulations(A) Secondary structure composition as function of amino acid residue and simulation time and (B) inter-strand twist angle as function of simulation time. The specific strand pairs are indicated. (C) One MD simulation of an I1067G substitution on β-strand 13 yielded large fluctuations in twist and eventually in breakage of the β-sheet. Shown here are (top) a snapshot of the G-box model at the end of this MD simulation and (bottom) inter-strand twist angles for the region surrounding the I1067G substitution.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4613516&req=5

Figure 2: Analysis of the G-box structure throughout 100 ns of atomistic MD simulations(A) Secondary structure composition as function of amino acid residue and simulation time and (B) inter-strand twist angle as function of simulation time. The specific strand pairs are indicated. (C) One MD simulation of an I1067G substitution on β-strand 13 yielded large fluctuations in twist and eventually in breakage of the β-sheet. Shown here are (top) a snapshot of the G-box model at the end of this MD simulation and (bottom) inter-strand twist angles for the region surrounding the I1067G substitution.
Mentions: In order to further investigate the unique nature of this domain, we used atomistic MD simulations to gain insight in the stability and flexibility of the structure. Starting from the crystallographic model 4LD1 we performed 100 ns-long simulations [5], throughout which the G-box structure remains stable as it retains the main chain hydrogen bonding network and secondary structure elements (Figure 2A; Supplementary Table S1; Supplementary Movie S1). Minimal distortions are visible in the terminal β-strands where the protein N- and C-termini tend to fold back and interact with the β-sheet; these distortions are transient and manifest as slightly higher than average inter-strand twist angles at the terminal β-strands (Figure 2B). The overall G-box β-sheet twist remains left-handed throughout the MD simulations although it flattens somewhat to 130±30° from the 168° starting point. In addition, an average length of seven amino acids is maintained for the majority of β-strands throughout the simulations (Figure 2A). Hence, the G-box structure retains an energetically favourable conformation with respect to its twist [30] and typical strand length [31]. Further domain motions in the MD simulations result in slight β-sheet bending, such that the average end-to-end distance is 72 Å compared with 75 Å in the starting model and transient fanning of β-strand termini as single hydrogen bonds break and reform.

Bottom Line: Molecular dynamics simulations support the stability of the G-box domain even in the face of truncations or amino acid substitutions.G-box fibrils were observed in crystals as well as in solution and are also supported by simulations.We conclude that the G-box domain may well represent the best analogue currently available for studies of exposed β-sheets, unencumbered by additional structural elements or severe aggregations problems.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University of Oxford, Oxford, OX1 3QU, U.K.

No MeSH data available.


Related in: MedlinePlus