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Thermodynamic selection of steric zipper patterns in the amyloid cross-beta spine.

Park J, Kahng B, Hwang W - PLoS Comput. Biol. (2009)

Bottom Line: Detailed analysis of individual energy terms reveals that these short peptides are not strained nor do they lose much conformational entropy upon incorporating into a beta-sheet bilayer.The selection of a bilayer pattern is determined mainly by the van der Waals and hydrophobic forces as a quantitative measure of shape complementarity among side chains between the beta-sheets.But the presence of charged side chains appears to kinetically drive anti-parallel beta-sheets to form at early stages of assembly, after which the bilayer formation is likely driven by energetics.

View Article: PubMed Central - PubMed

Affiliation: Department of Physics and Astronomy, Seoul National University, Seoul, Korea.

ABSTRACT
At the core of amyloid fibrils is the cross-beta spine, a long tape of beta-sheets formed by the constituent proteins. Recent high-resolution x-ray studies show that the unit of this filamentous structure is a beta-sheet bilayer with side chains within the bilayer forming a tightly interdigitating "steric zipper" interface. However, for a given peptide, different bilayer patterns are possible, and no quantitative explanation exists regarding which pattern is selected or under what condition there can be more than one pattern observed, exhibiting molecular polymorphism. We address the structural selection mechanism by performing molecular dynamics simulations to calculate the free energy of incorporating a peptide monomer into a beta-sheet bilayer. We test filaments formed by several types of peptides including GNNQQNY, NNQQ, VEALYL, KLVFFAE and STVIIE, and find that the patterns with the lowest binding free energy correspond to available atomistic structures with high accuracy. Molecular polymorphism, as exhibited by NNQQ, is likely because there are more than one most stable structures whose binding free energies differ by less than the thermal energy. Detailed analysis of individual energy terms reveals that these short peptides are not strained nor do they lose much conformational entropy upon incorporating into a beta-sheet bilayer. The selection of a bilayer pattern is determined mainly by the van der Waals and hydrophobic forces as a quantitative measure of shape complementarity among side chains between the beta-sheets. The requirement for self-complementary steric zipper formation supports that amyloid fibrils form more easily among similar or same sequences, and it also makes parallel beta-sheets generally preferred over anti-parallel ones. But the presence of charged side chains appears to kinetically drive anti-parallel beta-sheets to form at early stages of assembly, after which the bilayer formation is likely driven by energetics.

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Per-residue contribution to ΔGNB.(A) BBA1 of GNNQQNY (open square and open inverted triangle) and GNNAQNY (solid square and solid inverted triangle), where data for black square and red inverted triangle are based on the monomer energy calculated from the standard procedure in Fig. 1, and by the REMD simulation, respectively. Blue solid circle: the average B-factor of each residue in the 1YJP structure. Compared to Q4, A4 has higher ΔGNB relative to other residues. The inset shows the cross section of the Q4A filament after the simulation, indicating a well-formed steric zipper interface. (B) FBA1 (d = 4.85Å) of NNQQ. Square (circle) represents each residue in the upper (lower) layer of β-sheet and N1 is marked in the picture to distinguish the direction of peptides. (C) AregFF of KLVFFAE.
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pcbi-1000492-g012: Per-residue contribution to ΔGNB.(A) BBA1 of GNNQQNY (open square and open inverted triangle) and GNNAQNY (solid square and solid inverted triangle), where data for black square and red inverted triangle are based on the monomer energy calculated from the standard procedure in Fig. 1, and by the REMD simulation, respectively. Blue solid circle: the average B-factor of each residue in the 1YJP structure. Compared to Q4, A4 has higher ΔGNB relative to other residues. The inset shows the cross section of the Q4A filament after the simulation, indicating a well-formed steric zipper interface. (B) FBA1 (d = 4.85Å) of NNQQ. Square (circle) represents each residue in the upper (lower) layer of β-sheet and N1 is marked in the picture to distinguish the direction of peptides. (C) AregFF of KLVFFAE.

Mentions: Contribution by each residue to also supports that side chains at the steric zipper interface play a greater role compared to those exposed to water. For BBA1 of GNNQQNY, the residue-based profile of is consistent with its average B-factor in 1YJP (Fig. 12A). The greatest contribution is by Q4 located at the core of the steric zipper, followed by N2, revealing their stabilizing role. Odd-numbered residues facing water have comparatively higher . For G1, is the highest, thus it plays a minimal stabilizing role. This is consistent with the similarity between 1YJP and the structure without G1 (NNQQNY, PDB ID: 1YJO) [26]. Similar trends were observed for NNQQ and KLVFFAE, where side chains between the bilayer had greater contributions to (Fig. 12B and C).


Thermodynamic selection of steric zipper patterns in the amyloid cross-beta spine.

Park J, Kahng B, Hwang W - PLoS Comput. Biol. (2009)

Per-residue contribution to ΔGNB.(A) BBA1 of GNNQQNY (open square and open inverted triangle) and GNNAQNY (solid square and solid inverted triangle), where data for black square and red inverted triangle are based on the monomer energy calculated from the standard procedure in Fig. 1, and by the REMD simulation, respectively. Blue solid circle: the average B-factor of each residue in the 1YJP structure. Compared to Q4, A4 has higher ΔGNB relative to other residues. The inset shows the cross section of the Q4A filament after the simulation, indicating a well-formed steric zipper interface. (B) FBA1 (d = 4.85Å) of NNQQ. Square (circle) represents each residue in the upper (lower) layer of β-sheet and N1 is marked in the picture to distinguish the direction of peptides. (C) AregFF of KLVFFAE.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2723932&req=5

pcbi-1000492-g012: Per-residue contribution to ΔGNB.(A) BBA1 of GNNQQNY (open square and open inverted triangle) and GNNAQNY (solid square and solid inverted triangle), where data for black square and red inverted triangle are based on the monomer energy calculated from the standard procedure in Fig. 1, and by the REMD simulation, respectively. Blue solid circle: the average B-factor of each residue in the 1YJP structure. Compared to Q4, A4 has higher ΔGNB relative to other residues. The inset shows the cross section of the Q4A filament after the simulation, indicating a well-formed steric zipper interface. (B) FBA1 (d = 4.85Å) of NNQQ. Square (circle) represents each residue in the upper (lower) layer of β-sheet and N1 is marked in the picture to distinguish the direction of peptides. (C) AregFF of KLVFFAE.
Mentions: Contribution by each residue to also supports that side chains at the steric zipper interface play a greater role compared to those exposed to water. For BBA1 of GNNQQNY, the residue-based profile of is consistent with its average B-factor in 1YJP (Fig. 12A). The greatest contribution is by Q4 located at the core of the steric zipper, followed by N2, revealing their stabilizing role. Odd-numbered residues facing water have comparatively higher . For G1, is the highest, thus it plays a minimal stabilizing role. This is consistent with the similarity between 1YJP and the structure without G1 (NNQQNY, PDB ID: 1YJO) [26]. Similar trends were observed for NNQQ and KLVFFAE, where side chains between the bilayer had greater contributions to (Fig. 12B and C).

Bottom Line: Detailed analysis of individual energy terms reveals that these short peptides are not strained nor do they lose much conformational entropy upon incorporating into a beta-sheet bilayer.The selection of a bilayer pattern is determined mainly by the van der Waals and hydrophobic forces as a quantitative measure of shape complementarity among side chains between the beta-sheets.But the presence of charged side chains appears to kinetically drive anti-parallel beta-sheets to form at early stages of assembly, after which the bilayer formation is likely driven by energetics.

View Article: PubMed Central - PubMed

Affiliation: Department of Physics and Astronomy, Seoul National University, Seoul, Korea.

ABSTRACT
At the core of amyloid fibrils is the cross-beta spine, a long tape of beta-sheets formed by the constituent proteins. Recent high-resolution x-ray studies show that the unit of this filamentous structure is a beta-sheet bilayer with side chains within the bilayer forming a tightly interdigitating "steric zipper" interface. However, for a given peptide, different bilayer patterns are possible, and no quantitative explanation exists regarding which pattern is selected or under what condition there can be more than one pattern observed, exhibiting molecular polymorphism. We address the structural selection mechanism by performing molecular dynamics simulations to calculate the free energy of incorporating a peptide monomer into a beta-sheet bilayer. We test filaments formed by several types of peptides including GNNQQNY, NNQQ, VEALYL, KLVFFAE and STVIIE, and find that the patterns with the lowest binding free energy correspond to available atomistic structures with high accuracy. Molecular polymorphism, as exhibited by NNQQ, is likely because there are more than one most stable structures whose binding free energies differ by less than the thermal energy. Detailed analysis of individual energy terms reveals that these short peptides are not strained nor do they lose much conformational entropy upon incorporating into a beta-sheet bilayer. The selection of a bilayer pattern is determined mainly by the van der Waals and hydrophobic forces as a quantitative measure of shape complementarity among side chains between the beta-sheets. The requirement for self-complementary steric zipper formation supports that amyloid fibrils form more easily among similar or same sequences, and it also makes parallel beta-sheets generally preferred over anti-parallel ones. But the presence of charged side chains appears to kinetically drive anti-parallel beta-sheets to form at early stages of assembly, after which the bilayer formation is likely driven by energetics.

Show MeSH
Related in: MedlinePlus