Molecular dynamics simulations to investigate the relationship between the structural stability and amyloidogenesis of the wild-type and N-terminal hexapeptide deletion N6 2-microglobulin

Po Sheng Fang, Jian Hua Zhao, Hsuan Liang Liu, Kung Tien Liu, Jenn Tzong Chen, Wei Bor Tsai, Hsin Yi Lin, Hsu Wei Fang, Yih Ho

Research output: Contribution to journalArticle

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Abstract

β2-Microglobulin (β2m) forms amyloid fibrils in patients undergoing long-term haemodialysis, leading to dialysis-related amyloidosis. Proteolysis of the N-terminal region of β2m results in a truncation of the six N-terminal residues (δN6 β2m) in ̃30% of the β2m molecules extracted from ex vivo fibrils. The δN6 β2m has been shown to exhibit a higher tendency for self-association comparing to the wild-type (wt) β2m, particularly at neutral pH. In order to gain atomic insights into the early stages of amyloid formation of the wt and δN6 β2m, various molecular dynamics simulations were conducted to investigate the stability and dynamics of these two molecules at various temperatures and neutral pH in this study. Our results, in agreement with previous experimental results, indicate that the structural stability of the δN6 β2m is lower than that of the wt β2m. It can be attributed to fact that the removal of the N-terminal six residues results in the loss of the salt-bridge interaction between residues R3 and D59, leading to the increased solvent exposure of the K3 peptide. It further allows water molecules to destabilise the interior region of the K3 peptide, leading to the elongation between the B- and E-strands. It may further accelerate the conformational changes of the δN6 β2m, leading to the formation of amyloid fibrils more readily at neutral pH. Our results also suggest that the K3 peptide may be a potential initiation site of amyloid formation for the δN6 β2m due to its increased solvent exposure. We further suggest that fibril morphology of the δN6 β2m formed at neutral pH is similar to that of the wt β2m formed at low pH (1.5-3) since they adopt the similar conformation with the elongation between B- and E-strands for their partially unfolded myloidogenic intermediates.

Original languageEnglish
Pages (from-to)755-765
Number of pages11
JournalMolecular Simulation
Volume35
Issue number9
DOIs
Publication statusPublished - Aug 2009

Fingerprint

deletion
Structural Stability
structural stability
Amyloid
Molecular Dynamics Simulation
Deletion
Molecular dynamics
Peptides
molecular dynamics
Computer simulation
Molecules
peptides
Elongation
simulation
strands
elongation
Proteolysis
Dialysis
molecules
dialysis

Keywords

  • β2-microglobulin
  • δN6 β2m
  • Amyloidogenic intermediate
  • Dialysis-related amyloidosis
  • K3 peptide
  • Molecular dynamics simulations

ASJC Scopus subject areas

  • Condensed Matter Physics
  • Modelling and Simulation
  • Chemistry(all)
  • Chemical Engineering(all)
  • Materials Science(all)
  • Information Systems

Cite this

Molecular dynamics simulations to investigate the relationship between the structural stability and amyloidogenesis of the wild-type and N-terminal hexapeptide deletion N6 2-microglobulin. / Fang, Po Sheng; Zhao, Jian Hua; Liu, Hsuan Liang; Liu, Kung Tien; Chen, Jenn Tzong; Tsai, Wei Bor; Lin, Hsin Yi; Fang, Hsu Wei; Ho, Yih.

In: Molecular Simulation, Vol. 35, No. 9, 08.2009, p. 755-765.

Research output: Contribution to journalArticle

Fang, Po Sheng ; Zhao, Jian Hua ; Liu, Hsuan Liang ; Liu, Kung Tien ; Chen, Jenn Tzong ; Tsai, Wei Bor ; Lin, Hsin Yi ; Fang, Hsu Wei ; Ho, Yih. / Molecular dynamics simulations to investigate the relationship between the structural stability and amyloidogenesis of the wild-type and N-terminal hexapeptide deletion N6 2-microglobulin. In: Molecular Simulation. 2009 ; Vol. 35, No. 9. pp. 755-765.
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abstract = "β2-Microglobulin (β2m) forms amyloid fibrils in patients undergoing long-term haemodialysis, leading to dialysis-related amyloidosis. Proteolysis of the N-terminal region of β2m results in a truncation of the six N-terminal residues (δN6 β2m) in ̃30{\%} of the β2m molecules extracted from ex vivo fibrils. The δN6 β2m has been shown to exhibit a higher tendency for self-association comparing to the wild-type (wt) β2m, particularly at neutral pH. In order to gain atomic insights into the early stages of amyloid formation of the wt and δN6 β2m, various molecular dynamics simulations were conducted to investigate the stability and dynamics of these two molecules at various temperatures and neutral pH in this study. Our results, in agreement with previous experimental results, indicate that the structural stability of the δN6 β2m is lower than that of the wt β2m. It can be attributed to fact that the removal of the N-terminal six residues results in the loss of the salt-bridge interaction between residues R3 and D59, leading to the increased solvent exposure of the K3 peptide. It further allows water molecules to destabilise the interior region of the K3 peptide, leading to the elongation between the B- and E-strands. It may further accelerate the conformational changes of the δN6 β2m, leading to the formation of amyloid fibrils more readily at neutral pH. Our results also suggest that the K3 peptide may be a potential initiation site of amyloid formation for the δN6 β2m due to its increased solvent exposure. We further suggest that fibril morphology of the δN6 β2m formed at neutral pH is similar to that of the wt β2m formed at low pH (1.5-3) since they adopt the similar conformation with the elongation between B- and E-strands for their partially unfolded myloidogenic intermediates.",
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AU - Fang, Po Sheng

AU - Zhao, Jian Hua

AU - Liu, Hsuan Liang

AU - Liu, Kung Tien

AU - Chen, Jenn Tzong

AU - Tsai, Wei Bor

AU - Lin, Hsin Yi

AU - Fang, Hsu Wei

AU - Ho, Yih

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N2 - β2-Microglobulin (β2m) forms amyloid fibrils in patients undergoing long-term haemodialysis, leading to dialysis-related amyloidosis. Proteolysis of the N-terminal region of β2m results in a truncation of the six N-terminal residues (δN6 β2m) in ̃30% of the β2m molecules extracted from ex vivo fibrils. The δN6 β2m has been shown to exhibit a higher tendency for self-association comparing to the wild-type (wt) β2m, particularly at neutral pH. In order to gain atomic insights into the early stages of amyloid formation of the wt and δN6 β2m, various molecular dynamics simulations were conducted to investigate the stability and dynamics of these two molecules at various temperatures and neutral pH in this study. Our results, in agreement with previous experimental results, indicate that the structural stability of the δN6 β2m is lower than that of the wt β2m. It can be attributed to fact that the removal of the N-terminal six residues results in the loss of the salt-bridge interaction between residues R3 and D59, leading to the increased solvent exposure of the K3 peptide. It further allows water molecules to destabilise the interior region of the K3 peptide, leading to the elongation between the B- and E-strands. It may further accelerate the conformational changes of the δN6 β2m, leading to the formation of amyloid fibrils more readily at neutral pH. Our results also suggest that the K3 peptide may be a potential initiation site of amyloid formation for the δN6 β2m due to its increased solvent exposure. We further suggest that fibril morphology of the δN6 β2m formed at neutral pH is similar to that of the wt β2m formed at low pH (1.5-3) since they adopt the similar conformation with the elongation between B- and E-strands for their partially unfolded myloidogenic intermediates.

AB - β2-Microglobulin (β2m) forms amyloid fibrils in patients undergoing long-term haemodialysis, leading to dialysis-related amyloidosis. Proteolysis of the N-terminal region of β2m results in a truncation of the six N-terminal residues (δN6 β2m) in ̃30% of the β2m molecules extracted from ex vivo fibrils. The δN6 β2m has been shown to exhibit a higher tendency for self-association comparing to the wild-type (wt) β2m, particularly at neutral pH. In order to gain atomic insights into the early stages of amyloid formation of the wt and δN6 β2m, various molecular dynamics simulations were conducted to investigate the stability and dynamics of these two molecules at various temperatures and neutral pH in this study. Our results, in agreement with previous experimental results, indicate that the structural stability of the δN6 β2m is lower than that of the wt β2m. It can be attributed to fact that the removal of the N-terminal six residues results in the loss of the salt-bridge interaction between residues R3 and D59, leading to the increased solvent exposure of the K3 peptide. It further allows water molecules to destabilise the interior region of the K3 peptide, leading to the elongation between the B- and E-strands. It may further accelerate the conformational changes of the δN6 β2m, leading to the formation of amyloid fibrils more readily at neutral pH. Our results also suggest that the K3 peptide may be a potential initiation site of amyloid formation for the δN6 β2m due to its increased solvent exposure. We further suggest that fibril morphology of the δN6 β2m formed at neutral pH is similar to that of the wt β2m formed at low pH (1.5-3) since they adopt the similar conformation with the elongation between B- and E-strands for their partially unfolded myloidogenic intermediates.

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