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In Silico Study of an Alzheimer’s disease protein ( A β ). Fibril Entanglement. Fibril. Plaque. 100nm. A β. A ED VGSN K GA. 10nm. 1. 21. 30. 40. Experimental Background Experiments suggest Aβ(21-30) decapeptide may be the nucleating region for folding of full Aβ(1-40) peptide.

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In Silico Study of an Alzheimer’s disease protein (Aβ)

Fibril Entanglement

Fibril

Plaque

100nm

AEDVGSNKGA

10nm

1

21

30

40


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  • Experimental Background

  • Experiments suggest Aβ(21-30) decapeptide may be the nucleating region for folding of full Aβ(1-40) peptide.

Aβ(21-30) Relevant to Development of AD

  • What is the Question?

  • To determine the fold of Aβ(21-30) with atomic detail and find the stabilizing interactions.

  • How does it help?

  • The fold of Aβ(21-30) may provide plausible scenarios for the initial stages of fibril formation of full Aβ(1-40).

  • Identification of amino acids important for folding stability may lead to strategies to

  • prevent fibril formation.

  • What did we Find?

  • Aβ(21-30) adopts a loop conformation with center in S26, stabilized by hydrophobic interactions between V24 and K28.

  • There is a value for the strength of the electrostatic interaction that optimizes the stability of the loop.


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K28

K28

S26

S26

V24

V24

Experiments (our Collaborators)

Nuclear Magnetic Resonance data leads to two model structures of Aβ(21-30) in solution:

K28 below loop

K28 above loop

  • Aβ(21-30) adopts a loop conformation.

  • V24 and K28 are close.

  • The two model structures differ in the orientation of K28. Which one is true?

Lazo et at.,submitted to J. Mol. Biol.


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Simulations(my work)

  • Discrete Molecular Dynamics simulations of Aβ(21-30) in a cubic box of 40 Å with periodic boundary conditions for 50ns.

  • kBT=0.592 Kcal/mol (room temperature).

  • We perform simulations for different electrostatic interaction (EI) strengths:

  • 0.00 < EI < 1.5 Kcal/mol (typical in the surface of proteins)

  • 1.50 < EI < 2.5 Kcal/mol (typical in the interior of proteins)

  • Hydrogen-Bond strength = 3.5 Kcal/mol (typical in the surface of proteins)

  • HPvalues in the range-9.3<HP<1.3 Kcal/mol (negative stands for repulsive)


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K28

V24

S26

Simulations Results

V-K Unpacked

V

V-K Packed

K

Solvent Accesible Surface (Å2)

T.H.M.:

  • Hydrophobic interactions responsible for loop formation..

  • Electrostatic interaction of 1.5Kcal/mol optimizes loop stability.


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E22

D23

K28

Simulation Results (II)

The unpacked conformations at EI=2.5Kcal/mol have strong electrostatic interactions!

E22···K28

D23···K28

E22···K28

D23···K28

p=0.48

p=0.29

p=0.23

Hypotheis for Future work: We hypothesize that Aβ(21-30) undergoes partial unpacking of V24···K28 contacts and form D23···K28 electrostatic interactions upon fibril formation.


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n

v

E22

D23

K28

Simulation Results (III)

P() x 10-3

K28

S26

V24

(deg)

K28 below

loop plane

K28 above

loop plane

THM: Electrostatic interaction stabilizes K28 above the loop plane.

E22···K28

D23···K28


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B- B+

0.0 1 5

1.5 6 16

2.5 5 21

B- B+

0.0 1 1

1.5 7 9

2.5 11 13

Simulation Results (IV)

S

K

V

D

THM : only electrostatic interactions between E22 and K28 correlate with the orientation of K28 above the loop.


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V

S

K

D

E

K

Conclusions

  • Aβ(21-30) adopts a loop conformation centered at S26,

  • stabilized by hydrophobic interactions between V24 and K28.

  • There is a particular electrostatic interaction strength that

  • optimize the stability of the loop conformations.

  • Electrostatic interactions strengths typical of the interior of proteins destabilize the

  • loop conformations and form strong electrostatic interactions, preferentially D23···K28.

Future Work

  • Verify the hypothesis that Aβ(21-30) undergoes partial unfolding of V24-K28 and

  • formation of electrostatic interaction D23-K28 upon fibril formation with simulation

  • studies of many Ab(21-30).


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Thank you!

Collaborators

Sergey V. Buldyrev# Luis Cruz*

Feng Ding† Nikolay Dokholyan†

Alfonso Lam Ng* Noel Lazo¶

Manuel Marques§ Shouyong Peng*

Eugene Shakhnovich‡ David B. Teplow ¶

Brigita Urbanc* Sijung Yun*

*Center for Polymer Studies and Dept of Physics, Boston Univ., Boston MA, USA.

†Dept of Biochemistry and Biophysics, School of Medicine, Univ. of North Carolina at Chapel Hill,

Chapel Hill NC, USA.

# Dept of Physics, Yeshiva University, New York NY, USA.

‡Department of Chemistry and Chemical Biology, Harvard Univ., Cambridge MA, USA

§ Dept. of Physics and Condensed matter C IV, Univ. Autonoma Madrid, Madrid, Spain.

¶Center for Neurological Diseases, Brigham and Women’s Hospital and Dept. of Neurology, Harvard

Medical School, Boston MA, USA


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Ab Model

D23

N27

A21

G25

G27

V24

S26

A30

E22

K28

Three bonding types describe the protein geometry:

1st neigh.

2nd neigh.

3rd neigh.

(covalent)

(angle)

(dihedral)

1

1

1

1

2

4

2

2

4

4

3

3

3


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electrostatics

hydropathy

Hydrogen Bond

-

+

N

O

C

N

+

+

+

-

-

-

O

EI

Ab Model (cont.)

-

-

-

-

Three types of atomic interactions:

+

HP


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An Example of Dihedral Potential


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Hydropathy Interactions

When two atoms i and j make a contact, they interact with a hydropathy strength.

HPij=HPi+HPj ,

HP: free energy of transfer

HP

Aqueous Phase

Gas Phase

SAS :solvent accesible surface

σ: atomic solvation parameter

HPi=ΔSASi · σi


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Arginine (R)

Lysine (K)

ΔFR=σC ·(ΣCi SASCi) +σN ·(ΣNi SASNi)

ΔFK=σC ·(ΣCi SASCi) +σN ·SASNi

Solve for σC and σN

Atomic Solvation Parameters

HPi=ΔSASi · σi


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Two Representative Conformations

K28 below loop plane

K28 above loop plane

E22-K28 interaction shown


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i

j

i

i

j

j

Results: Loop Flexibility

σ

Δd

  • The loop is rigid only when close to the turn

  • E22-K28 and D23-K28 salt-bridges increase loop rigidity.

  • When loop forms, distances E22-K28, D23-K28 and V24-K28 corresponding to attractive

  • interactions decrease the most.

  • Flexibility of the loop strands allows K28 to flip-flop its orientation with respect to the loop


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