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)
Aβ(21-30) Relevant to Development of AD
Experiments (our Collaborators)
Nuclear Magnetic Resonance data leads to two model structures of Aβ(21-30) in solution:
K28 below loop
K28 above loop
Lazo et at.,submitted to J. Mol. Biol.
Solvent Accesible Surface (Å2)
Simulation Results (II)
The unpacked conformations at EI=2.5Kcal/mol have strong electrostatic interactions!
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.
Simulation Results (III)
P() x 10-3
THM: Electrostatic interaction stabilizes K28 above the loop plane.
0.0 1 5
1.5 6 16
2.5 5 21
0.0 1 1
1.5 7 9
2.5 11 13
Simulation Results (IV)
THM : only electrostatic interactions between E22 and K28 correlate with the orientation of K28 above the loop.
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
Three bonding types describe the protein geometry:
Ab Model (cont.)
Three types of atomic interactions:
When two atoms i and j make a contact, they interact with a hydropathy strength.
HP: free energy of transfer
SAS :solvent accesible surface
σ: atomic solvation parameter
HPi=ΔSASi · σi
ΔFR=σC ·(ΣCi SASCi) +σN ·(ΣNi SASNi)
ΔFK=σC ·(ΣCi SASCi) +σN ·SASNi
Solve for σC and σN
Atomic Solvation Parameters
HPi=ΔSASi · σi
K28 below loop plane
K28 above loop plane
E22-K28 interaction shown
Results: Loop Flexibility