1. Brigita Urbanc, Luis Cruz, Shouyong Peng, Jose Borreguero, Alfonso Lam
Aggregation phenomena relevant to Alzheimer’s Disease: Statistical physics approach
Sijung Yun
Collaborators:
Brigita Urbanc, Luis Cruz, Shouyong Peng, Jose Borreguero, Alfonso Lam
Advisor: H.E. Stanley

2. Outline Alzheimer’s disease & Aβ- protein
Simulation of Aβ-proteins folding and aggregation
My research topic is computer simulation of protein folding and its aggregation. The protein that I chose to study is related to Alzheimer’s disease. So in the beginning, I am going to talk about the Alzheimer’s disease. And the relationship between Alzheimer’s disease and Amyloid beta protein.
Mainly, there are two kind of amyloid beta protein, which is Ab40 & Ab42. For Ab42, 42 means that there are 42 amino acids. If you take out the last two amino acids from Ab42 protein, then it becomes Ab40. But they have very different characteristics. One of the differences is aggregation.
Prepare two test tubes. Put many Ab40 protein in one test tube, and put many Ab42 in the other test tube. And wait for a few days. Then you will see that Ab42 proteins get together, and form a fibril( which you can think as a fiber). But Ab40 proteins almost remain individually without aggregation. Why is this aggregation property important to

3. Alzheimer’s disease is related to Amyloid β-proteins(Aβ)
Over 50% for the people over 85 years old
Increasing forgetfulness, etc.
Clinically, a dementia characterized by fibril made of amyloid β-proteins(Aβ) and tangles made of τ-protein in brain
Amyloid β-proteins(Aβ) come in two forms:
Aβ40: 1DAEFR 6HDSGY 11EVHHQ 16KLVFF 21AEDVG 26SNKGA 31IIGLM 36VGGVV
Aβ42: 1DAEFR 6HDSGY 11EVHHQ 16KLVFF 21AEDVG 26SNKGA 31IIGLM 36VGGVV 41I42A
Oligomers of Aβ-40 and Aβ-42 are neurotoxic
Oligomers of Aβ-42 are more neurotoxic than that of Aβ-40
Pictures of plaque and tangles.

4. What did we do? Why?
We used “Discrete Molecular Dynamics” for the study of oligomerization of Aβ-40 and Aβ-42 in atomic detail
Why?
Experiment cannot show how Aβ-40 protein and Aβ-42 protein oligomerize in atomic detail
Conventional molecular dynamics cannot study oligomerization (too much CPU time)

5. Discrete Molecular Dynamics(DMD)
Conventional Molecular Dynamics
Discrete Molecular Dynamics

6. DMD with hydrophobic interaction
Hydrophobicity is the driving force of the protein folding and aggregation
Hydrophobicity appears as “the effective attraction” between hydrophobic particles
Hydrophilicity appears as “the effective repulsion” between hydrophilic particles
Hydrophobic attraction
Distance(Å)
P.E.
3.07Å
7.5 Å
Hydrophilic repulsion
Distance(Å)
P.E.
3.07Å
7.5 Å

7. Finally, Statistical analysis
Running
DMD
Simulation
Motivation to study 8 sets(or trajectories) not one set.
Prepare 8 sets of 32 proteins
for each Aβ40 and Aβ42
Get 8 trajectories
for each Aβ40 and Aβ42
Finally, Statistical analysis

8. Simulation results (1) Oligomer Size distribution
Explain about concentration
Ref) Bital et al. (2003) Proc. Natl. Acad. Sci. USA 100(1) 330-5

9. How to read a contact map
(35,18)
(39,36)
1DAEFR 6HDSGY 11EVHHQ 16KLVFF 21AEDVG 26SNKGA 31I I GLM 36VGGVV 41I 42A

10. Simulation results(2) How “monomers” fold as time goes on
1DAEFR 6HDSGY 11EVHHQ 16KLVFF 21AEDVG 26SNKGA 31I I GLM 36VGGVV 41I 42A
Monomers fold from “C terminal region”(Around 40 or 42) to “N terminal region”(around 1)

11. Simulation results (3) “Pentamers” of Aβ-40 and Aβ-42
Explain about concentration
“N terminal”(Around 1) of Aβ42 is more stretched than that of Aβ40
Ref) Urbanc B, Cruz L,Yun S, Buldyrev SV, Bitan G, Teplow DB, Stanley HE,
(2004) Proc. Natl. Acad. Sci. USA

12. Ongoing work: Adding Coulombic interaction
Some amino acids are charged.
Negatively charged amino acids: D-, E-
Positively charged amino acids: R+, K+
1D-AE-FR+ 6HD-SGY 11E-VHHQ 16K+LVFF 21AE-D-VG 26SNK+GA 31I I GLM 36VGGVV 41I 42A

13. Analysis ongoing: When electrostatic interaction is added
Sharper  better defined structure

14. Conclusions “Monomers” fold from C terminal to N terminal
N terminals of Aβ-42 oligomers are more stretched out than those of Aβ-40 oligomers
Simulation shows there is a significant difference between aggregation of Aβ-40 and Aβ-42
Simulation gives insights why Aβ-40 and Aβ-42 aggregate differently;
Reason; The hydrophobicity of 41th and 42th amino acids causes the structural difference in folding

15. Primary structure of Aβ(1-42)
1D-AE-FR+ 6HD-SGY E-VHHQ K+LVFF
21AE-D-VG 26SNK+GA I I GLM VGGVV
{41I 42A}
(Hydrophobic)
I:Ile V:Val L:Leu F:Phe C:Cys M:Met A: Ala
(Neutral in hydrophobicity)
S:Ser T:Thr W:Trp P:Pro Y:Tyr G:Gly
(Hydrophilic)
R+:Arg K+:Lys D-:Asp E-:Glu N:Asn Q:Gln H:His

16. Simulation additional results Prediction of secondary structure of monomers (no electrostatic interaction)
Initial
103 Steps
104 Steps
105 Steps
Black: Aβ40
Red: Aβ42