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Revealing the Mechanistic Pathway of Cholinergic inhibition of Alzheimer’s disease by Donepezil: A Metadynamics Simulation Study
Shibaji Ghosh,a,b Kalyanashis Jana,a,b and Bishwajit Ganguly*a,b
aComputation and Simulation Unit (Analytical and Environmental Science Division and Centralized
Instrument Facility), CSIR-Central Salt and Marine Chemicals Research Institute, Bhavnagar,
Gujarat, India-364 002.bAcademy of Scientific and Innovative Research, CSIR-CSMCRI, Bhavnagar, Gujarat, India-364
002.
Fax: (+91)-278-2567562, Telephone: (+91)-278-2567760 Ext: 6770
E-mail: [email protected]; [email protected]
Electronic supplementary information
hAChE & Donepezil Crystal
0 1 2 3 4 5 6 7 8-100
-90
-80
-70
-60
-50
-40
-30
-20
-10
0
10
PMF
(kJ/
mol
)
COM Separation (nm)
0.02 ns 1 ns 5 ns 10 ns 15 ns 20 ns 30 ns
Ser203 & Donepezil
0 1 2 3 4 5 6 7 8-100
-90
-80
-70
-60
-50
-40
-30
-20
-10
0
10
PMF
(kJ/
mol
)
COM Separation (nm)
0.02 ns 1 ns 5 ns 10 ns 15 ns 20 ns 30 ns
Glu334 & Donepezil
0 1 2 3 4 5 6 7 8-100
-90
-80
-70
-60
-50
-40
-30
-20
-10
0
10
PMF
(kJ/
mol
)
COM Separation (nm)
0.02 ns 1 ns 5 ns 10 ns 15 ns 20 ns 30 ns
His447 & Donepezil
Fig. S1 The free energy profiles as a function of a CV namely Ser203, Glu334 and His447 with donepezil crystal were plotted at different time and compared with other to access the convergence of a well-tempered metadynamics simulation.
Electronic Supplementary Material (ESI) for Physical Chemistry Chemical Physics.This journal is © the Owner Societies 2019
hAChE & Docked Donepezil
0 1 2 3 4 5 6 7 8-100
-90
-80
-70
-60
-50
-40
-30
-20
-10
0
10
PMF
(kJ/
mol
)
COM Separation (nm)
0.02 ns 1 ns 5 ns 10 ns 15 ns 20 ns 30 ns
Ser203 & Donepezil
0 1 2 3 4 5 6 7 8-100
-90
-80
-70
-60
-50
-40
-30
-20
-10
0
10
PMF
(kJ/
mol
)
COM Separation (nm)
0.02 ns 1 ns 5 ns 10 ns 15 ns 20 ns 30 ns
Glu334 & Donepezil
0 1 2 3 4 5 6 7 8-100
-90
-80
-70
-60
-50
-40
-30
-20
-10
0
10
PMF
(kJ/
mol
)
COM Separation (nm)
0.02 ns 1 ns 5 ns 10 ns 15 ns 20 ns 30 ns
His447 & Donepezil
Fig. S2 The free energy profiles as a function of a CV namely Ser203, Glu334 and His447 with docked donepezil were plotted at different time and compared with other to access the convergence of a well-tempered metadynamics simulation.
hAChE & Donepezil Crystal
0 10000 20000 300000.0
1.9
3.8
5.7
7.60.0
2.1
4.2
6.3
0.0
2.3
4.6
6.9
Time (ps)
CV1
CO
M (n
m)
CV2
CV3
Fig. S3 Time evaluation plot of the examined CVs (CV1 = Ser203 & Donepezil; CV2 = His447 & Donepezil; CV3 = Glu334 & Donepezil) of the well-tempered metadynamics simulation for Donepezil crystal.
hAChE & Docked Donepezil
0 10000 20000 300000
2
4
6
80.0
2.3
4.6
6.9
0.0
2.3
4.6
6.9
Time (ps)
CV1
CO
M S
epar
atio
n (n
m)
CV2
CV3
Fig. S4 Time evaluation plot of the examined CVs (CV1 = Ser203 & donepezil; CV2 = His447 & Donepezil; CV3 = Glu334 & Donepezil) of the well-tempered metadynamics simulation for docked donepezil.
