Molecular dynamics study to investigate the effect of chemical substitutions of methionine 35 on the secondary structure of the amyloid β(Aβ(1-42)) monomer in aqueous solution

Luciano Triguero, Rajiv Singh, Rajeev Prabhakar

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Abstract

In this study, all-atom molecular dynamics simulations in the explicit water solvent are performed to investigate conformational changes in the secondary structure of the Aβ(1-42) monomer associated with the substitution of the Cγ-methylene position of the Met35 amino acid residue by sulfoxide (Met35(O)), sulfone (Met35-(O2)), and norleucine (Met35(CH2)). The effects of these substitutions on the structural changes that occur in three distinct regions (the central hydrophobic core (CHC) region 17-21 (LVFFA), stable turn segment 24-27 (VGSN), and second hydrophobic region 29-35 (GAIIGLM)) of all monomers have been analyzed in detail, and results are compared with experiments. Our 20 ns simulations indicate that the most significant changes take place in the second hydrophobic region of the Met35(0) and Met35(O) monomers. However, for the Met35(CH 2) monomer, this region does not exhibit significant deviations. In comparison to the wild-type (WT)-Aβ(1-42) monomer, for Met35(O) the second hydrophobic region is characterized by the formation of internal β-sheets separated by stable turns, whereas for Met35(O2) it exhibits a more helical conformation. These substantial changes in the secondary structure can be explained in terms of an increase in the computed dipole moment and solvent accessible surface area (SASA) per residue of these substituents. These structural modifications can affect interaction between monomers, which in turn may influence the oligomerization process involved in Alzheimer's disease (AD).

Original languageEnglish
Pages (from-to)2159-2167
Number of pages9
JournalJournal of Physical Chemistry B
Volume112
Issue number7
DOIs
StatePublished - Feb 21 2008

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methionine
Amyloid
Methionine
Molecular dynamics
Substitution reactions
monomers
Monomers
substitutes
molecular dynamics
aqueous solutions
sulfoxide
norleucine
Norleucine
Oligomerization
Sulfones
sulfones
Dipole moment
methylene
amino acids
Conformations

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry

Cite this

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title = "Molecular dynamics study to investigate the effect of chemical substitutions of methionine 35 on the secondary structure of the amyloid β(Aβ(1-42)) monomer in aqueous solution",
abstract = "In this study, all-atom molecular dynamics simulations in the explicit water solvent are performed to investigate conformational changes in the secondary structure of the Aβ(1-42) monomer associated with the substitution of the Cγ-methylene position of the Met35 amino acid residue by sulfoxide (Met35(O)), sulfone (Met35-(O2)), and norleucine (Met35(CH2)). The effects of these substitutions on the structural changes that occur in three distinct regions (the central hydrophobic core (CHC) region 17-21 (LVFFA), stable turn segment 24-27 (VGSN), and second hydrophobic region 29-35 (GAIIGLM)) of all monomers have been analyzed in detail, and results are compared with experiments. Our 20 ns simulations indicate that the most significant changes take place in the second hydrophobic region of the Met35(0) and Met35(O) monomers. However, for the Met35(CH 2) monomer, this region does not exhibit significant deviations. In comparison to the wild-type (WT)-Aβ(1-42) monomer, for Met35(O) the second hydrophobic region is characterized by the formation of internal β-sheets separated by stable turns, whereas for Met35(O2) it exhibits a more helical conformation. These substantial changes in the secondary structure can be explained in terms of an increase in the computed dipole moment and solvent accessible surface area (SASA) per residue of these substituents. These structural modifications can affect interaction between monomers, which in turn may influence the oligomerization process involved in Alzheimer's disease (AD).",
author = "Luciano Triguero and Rajiv Singh and Rajeev Prabhakar",
year = "2008",
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T1 - Molecular dynamics study to investigate the effect of chemical substitutions of methionine 35 on the secondary structure of the amyloid β(Aβ(1-42)) monomer in aqueous solution

AU - Triguero, Luciano

AU - Singh, Rajiv

AU - Prabhakar, Rajeev

PY - 2008/2/21

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N2 - In this study, all-atom molecular dynamics simulations in the explicit water solvent are performed to investigate conformational changes in the secondary structure of the Aβ(1-42) monomer associated with the substitution of the Cγ-methylene position of the Met35 amino acid residue by sulfoxide (Met35(O)), sulfone (Met35-(O2)), and norleucine (Met35(CH2)). The effects of these substitutions on the structural changes that occur in three distinct regions (the central hydrophobic core (CHC) region 17-21 (LVFFA), stable turn segment 24-27 (VGSN), and second hydrophobic region 29-35 (GAIIGLM)) of all monomers have been analyzed in detail, and results are compared with experiments. Our 20 ns simulations indicate that the most significant changes take place in the second hydrophobic region of the Met35(0) and Met35(O) monomers. However, for the Met35(CH 2) monomer, this region does not exhibit significant deviations. In comparison to the wild-type (WT)-Aβ(1-42) monomer, for Met35(O) the second hydrophobic region is characterized by the formation of internal β-sheets separated by stable turns, whereas for Met35(O2) it exhibits a more helical conformation. These substantial changes in the secondary structure can be explained in terms of an increase in the computed dipole moment and solvent accessible surface area (SASA) per residue of these substituents. These structural modifications can affect interaction between monomers, which in turn may influence the oligomerization process involved in Alzheimer's disease (AD).

AB - In this study, all-atom molecular dynamics simulations in the explicit water solvent are performed to investigate conformational changes in the secondary structure of the Aβ(1-42) monomer associated with the substitution of the Cγ-methylene position of the Met35 amino acid residue by sulfoxide (Met35(O)), sulfone (Met35-(O2)), and norleucine (Met35(CH2)). The effects of these substitutions on the structural changes that occur in three distinct regions (the central hydrophobic core (CHC) region 17-21 (LVFFA), stable turn segment 24-27 (VGSN), and second hydrophobic region 29-35 (GAIIGLM)) of all monomers have been analyzed in detail, and results are compared with experiments. Our 20 ns simulations indicate that the most significant changes take place in the second hydrophobic region of the Met35(0) and Met35(O) monomers. However, for the Met35(CH 2) monomer, this region does not exhibit significant deviations. In comparison to the wild-type (WT)-Aβ(1-42) monomer, for Met35(O) the second hydrophobic region is characterized by the formation of internal β-sheets separated by stable turns, whereas for Met35(O2) it exhibits a more helical conformation. These substantial changes in the secondary structure can be explained in terms of an increase in the computed dipole moment and solvent accessible surface area (SASA) per residue of these substituents. These structural modifications can affect interaction between monomers, which in turn may influence the oligomerization process involved in Alzheimer's disease (AD).

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