Prediction of the structural changeof the amyloid β protein at the fibril
end: DFT-RISM study
Yasuhiro Oishi
Graduate schoool of science, Univesity of Hyogo

RIKEN Symposium
Second Workshop on Fundamentals in Density Functional Theory(2024/2/21)

Acknowledgement
・Discussion on experiments【Prof. H. Ogi and Prof. K. Nakajima (U. Osaka)】・Comment on RISM calculation【Prof. M. Otani and Prof. S. Hagiwara (U. Tsukuba)】
・Discussion on calculation model and DFT calculation【Prof. K. Kusakabe and Prof. M. Kitatani (U. Hyogo)】
Reference・ Y. Oishi, H. Ogi, S. Hagiwara, M. Otani, K. Kusakabe. ACS omega, 7, 35,31120-31125 (2022).
・ Y. Oishi, M. Kitatani, and K. Kusakabe. Beilstein Archives, 2023, 1, 59(2023)
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Amyloid β aggregates to form fibril.
Amyloid fibril is an aggregate of proteins.
Fibril axis

CHNO

Amyloid fibril

An example of amyloid β(Aβ) (PDB: 6OIZ)
viewed down the fibril axis

Formation of fibril causes Altzheimer disease.
elongation
Formation of nucleus
takes long time.

nucleusrapid reaction

fibrilTo prevent the onset of disease, the fibril should bedisaggregated into monomers.

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Disaggregation by fragmentation
Disaggregation behavior observed by fluorescence microscope
K, Noi., et al., Anal. Chem. (2021)

This is not a desirable disaggregation, because fragmentation
increases elongated fibrils.
Xue, W. F., et al., J. Biol. Chem. (2009)
Fragmentation

elongation

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Disaggregation by dissociation of monomer
fibrilfibrilfibril＋
Monomer dissociatesfrom the fibril-end.

＋・・・

Formation of fibril frommonomeric state takes long time.

The number of fibrils unchanges.

Desireble !

Purpose of this study
Understanding motion of Aβ at the fibril end leading
to the disaggregation based on DFT approach.
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Calculation model for Aβ at the fibril-end
Aβ dimer was used as a model for fibril-end strucure.

upper layer

Top view

fibrilSide view

Water

lower layer

Water molecules were expressed as an ensemble-averaged
distribution function, determined by RISM (※).
(※) Reference interaction site model (RISM)
J. P. Hansen and I. R. McDonald, (Academic, London, 1976).

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Scheme of DFT-RISM method
RISM equation determines the total
and direct correlation functionℎ! (𝒓)(= 𝑔! 𝒓 − 1) and 𝑐! (𝒓).

Kovalenko, A; Hirata, F.
J. Chem. Phys. (1999).

Kohn-Sham equation withsolvation potential 𝑣"#$% (𝒓)determines electron density 𝑛(𝒓).

𝑢(𝒓) is the two-body interaction potential.

Free energy as a sum of DFT energy and solvation energy

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Computational details
Structural optimization by conventional DFT

Structural optimization by DFT-RISM

Computational details for DFT

Computational details for RISM・Energy functional : PBEsol+D3

・Solvent

・Energy cutoff for wavefunction: 25 Ry・Temperature and density : 300 K, 1 g/cm3

・Energy cutoff for charge: 250 Ry

・Lenard-Jones parameter for DFT particle：

・𝒌-mesh : Gamma point

Universal force field: water (SPC model)

All calculations were carried out using Quantum ESPRESSO.

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Result of the structural optimization by DFT
Structural optimization by DFT without water

Top view

Rotation

Side view

dissociated part

Conformation 1Conformation 2
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Result of the structural optimization by DFT
Structural optimization by DFT without water

Top viewRotation

Side view

dissociated part

Conformation 1+ 2.75 eV

Conformation 2

Dissociation of upper layer requires huge energy loss.

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Result of the structural optimization by DFT

3.2Å
3.2Å

Conformation 1
2.9Å
2.8Å

2.9Å

Side view of Conformation 1

Conformation 2

The energy loss partly comes from the cleavage ofhydrogen bonds connecting two layers.

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Result of the structural optimization by DFT-RISM
Relative energy of conformation 2 to conformation 1

Conformation 1

Conformation 2+ 2.75 eV

in the vacuum (DFT)+ 1.58 eV

in water (DFT-RISM)

The dissociation of upper layer tends to happen moreeasily in water than in the vacuum.

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+0.01Top view[ 1/bohr-3 ]H-richTop view

Charge density distribution of waterO-rich

Side view-0.01

Side view

0.00

Conformation 1Conformation 2

Hydration of the polar portion exposed upon
dissociation improves the stability of conformation 2.

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Summary
Stable dimer structure of amyloid β protein wasdetermined by DFT and DFT-RISM.

dissociation

・Dissociation requires huge energy loss.
・Hydration lowers energy loss upon dissociation.

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