Abstract
Replica exchange molecular dynamics simulations (300 ns) were used to study the dimerization of amyloid β(1-40) (Aβ(1-40)) polypeptide. Configurational entropy calculations revealed that at physiological temperature (310 K, 37°C) dynamic dimers are formed by randomly docked monomers. Free energy of binding of the two chains to each other was -93.56±6.341 kJ mol-1. Prevalence of random coil conformations was found for both chains with the exceptions of increased β-sheet content from residues 16-21 and 29-32 of chain A and residues 15-21 and 30-33 of chain B with β-turn/β-bend conformations in both chains from residues 1-16, 21-29 of chain A, 1-16, and 21-29 of chain B. There is a mixed β-turn/β-sheet region from residues 33-38 of both chains. Analysis of intra- and interchain residue distances shows that, although the individual chains are highly flexible, the dimer system stays in a loosely packed antiparallel β-sheet configuration with contacts between residues 17-21 of chain A with residues 17-21 and 31-36 of chain B as well as residues 31-36 of chain A with residues 17-21 and 31-36 of chain B. Based on dihedral principal component analysis, the antiparallel β-sheet-loop-β-sheet conformational motif is favored for many low energy sampled conformations. Our results show that Aβ(1-40) can form dynamic dimers in aqueous solution that have significant conformational flexibility and are stabilized by collapse of the central and C-terminal hydrophobic cores with the expected β-sheet-loop-β-sheet conformational motif.
| Original language | English (US) |
|---|---|
| Journal | Proteins: Structure, Function and Bioinformatics |
| DOIs | |
| State | Accepted/In press - 2017 |
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All Science Journal Classification (ASJC) codes
- Structural Biology
- Biochemistry
- Molecular Biology
Cite this
Structural properties of amyloid β(1-40) dimer explored by replica exchange molecular dynamics simulations. / Watts, Charles R.; Gregory, Andrew J.; Frisbie, Cole P.; Lovas, Sándor.
In: Proteins: Structure, Function and Bioinformatics, 2017.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Structural properties of amyloid β(1-40) dimer explored by replica exchange molecular dynamics simulations
AU - Watts, Charles R.
AU - Gregory, Andrew J.
AU - Frisbie, Cole P.
AU - Lovas, Sándor
PY - 2017
Y1 - 2017
N2 - Replica exchange molecular dynamics simulations (300 ns) were used to study the dimerization of amyloid β(1-40) (Aβ(1-40)) polypeptide. Configurational entropy calculations revealed that at physiological temperature (310 K, 37°C) dynamic dimers are formed by randomly docked monomers. Free energy of binding of the two chains to each other was -93.56±6.341 kJ mol-1. Prevalence of random coil conformations was found for both chains with the exceptions of increased β-sheet content from residues 16-21 and 29-32 of chain A and residues 15-21 and 30-33 of chain B with β-turn/β-bend conformations in both chains from residues 1-16, 21-29 of chain A, 1-16, and 21-29 of chain B. There is a mixed β-turn/β-sheet region from residues 33-38 of both chains. Analysis of intra- and interchain residue distances shows that, although the individual chains are highly flexible, the dimer system stays in a loosely packed antiparallel β-sheet configuration with contacts between residues 17-21 of chain A with residues 17-21 and 31-36 of chain B as well as residues 31-36 of chain A with residues 17-21 and 31-36 of chain B. Based on dihedral principal component analysis, the antiparallel β-sheet-loop-β-sheet conformational motif is favored for many low energy sampled conformations. Our results show that Aβ(1-40) can form dynamic dimers in aqueous solution that have significant conformational flexibility and are stabilized by collapse of the central and C-terminal hydrophobic cores with the expected β-sheet-loop-β-sheet conformational motif.
AB - Replica exchange molecular dynamics simulations (300 ns) were used to study the dimerization of amyloid β(1-40) (Aβ(1-40)) polypeptide. Configurational entropy calculations revealed that at physiological temperature (310 K, 37°C) dynamic dimers are formed by randomly docked monomers. Free energy of binding of the two chains to each other was -93.56±6.341 kJ mol-1. Prevalence of random coil conformations was found for both chains with the exceptions of increased β-sheet content from residues 16-21 and 29-32 of chain A and residues 15-21 and 30-33 of chain B with β-turn/β-bend conformations in both chains from residues 1-16, 21-29 of chain A, 1-16, and 21-29 of chain B. There is a mixed β-turn/β-sheet region from residues 33-38 of both chains. Analysis of intra- and interchain residue distances shows that, although the individual chains are highly flexible, the dimer system stays in a loosely packed antiparallel β-sheet configuration with contacts between residues 17-21 of chain A with residues 17-21 and 31-36 of chain B as well as residues 31-36 of chain A with residues 17-21 and 31-36 of chain B. Based on dihedral principal component analysis, the antiparallel β-sheet-loop-β-sheet conformational motif is favored for many low energy sampled conformations. Our results show that Aβ(1-40) can form dynamic dimers in aqueous solution that have significant conformational flexibility and are stabilized by collapse of the central and C-terminal hydrophobic cores with the expected β-sheet-loop-β-sheet conformational motif.
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U2 - 10.1002/prot.25270
DO - 10.1002/prot.25270
M3 - Article
JO - Proteins: Structure, Function and Genetics
JF - Proteins: Structure, Function and Genetics
SN - 0887-3585
ER -