1. Computational Modelling of Receptor Ligand complex
associated to Fibromyalgia Syndrome Amit Kumar [email protected]
27-05-2015
2. Outline Quick Introduction to problem of Fibromyalgia
Motivation Key players Our methodological approach Building Model
Docking Molecular Dynamics Results Conclusion 2
3. Quick Introduction 3
4. Motivation Fibromyalgia pathogenesis unclear and no
biomarkers. Observed increase PC(14:0/0:0) and PC(16:0/0:0) in FMS
patients noted using plasma lipidomic analysis approach
metabolites. These metabolites had Platelet Activating Factor (PAF)
like structure. PAF : a potent phospholipid activator mediator of
many leukocyte (White Blood cell) functions, e.g. inflammation
4
15. PAFR-Ligand Binding region Ligands G (Binding free energy)
PAF -7.O kcal/mol PC(14:O/O:O) -7.1 kcal/mol PC(16:O/O:O) -5.1
kcal/mol Docking Energy 15
16. Molecular Dynamics: 1
17. Molecular Dynamics: 2
http://portfolio.scistyle.com/Publication-Quality-Science-Figures17
(1) (2) (3) (4)(5) Empirical Force Field equation Non-bonded terms
Bonded terms Electrostatics Van der Waals
18. Molecular Dynamics: 3 18 MD Engine3D coordinates Topology
file Parameter file New 3D coordinates at different time intervals
NAMD, AMBER, CHARMM, GROMACS, DLPOLY
19. TOPOLOGY File Topology RESI ALA 0.00 GROUP ATOM N NH1 -0.47
! | ATOM HN H 0.31 ! HN-N ATOM CA CT1 0.07 ! | HB1 ATOM HA HB 0.09
! | / GROUP ! HA-CA--CB-HB2 ATOM CB CT3 -0.27 ! |ATOM HB1 HA 0.09 !
| HB3 ATOM HB2 HA 0.09 ! O=C ATOM HB3 HA 0.09 ! | GROUP ! ATOM C C
0.51 ATOM O O -0.51 BOND CB CA N HN N CA BOND C CA C +N CA HA CB
HB1 CB HB2 CB HB3 DOUBLE O C IMPR N -C CA HN C CA +N O DONOR HN N
ACCEPTOR O C c ct1 ct3 nh1
20. PARAMETER File BONDS CT3 CT1 222.00 1.538 CT3 HA 322 1.1
CE1 CE1 440.000 1.3400 ANGLE CT3 CT1 HB 30.000 110.00 CT3 CT1 C
48.00 123.50 HA CT3 CT1 32.00 112.20 NH1 CT1 HB 23.00 118.00
DIHEDRAL CT3 CT1 C O O.2 1 180.0 HA CT3 CT1 NH1 0.5 2 180.0 c ct1
ct3 ha hb nh1 o
21. Mimicking Biological membrane Insertion of PAFr-ligand
complex into the membrane Start with a relaxed membrane-water
system
22. Movies
23. RMSD Analysis: LIGAND Measure of the deviation between the
atoms (usually the backbone atoms) with respect to starting
structure
24. RMSD helix Gui. et. al found large deviation of Helix 3 and
Helix 6: Related to PAFr activation
25. Hydrogen Bond interactions
26. Binding Free Energy Calculation MM-PBSA: Molecular
Mechanics- Poisson Bolzmann Surface Area Gsolv = EPB/EGB + ECAVITY
EPB/EGB = the electrostatic contribution to the free energy
calculated by PB or GB ECAVITY = nonpolar contribution to the
solvation free energy calculated by an empirical model. 26
27. Interaction Picture
28. Conclusions PC(14:0/0:0) and PC(16:0/0:0) ligands are
slightly more flexible than PAF, but overall similar binding energy
~11 kcal/mol to PAFR. RMSD variations in key intra-membrane domains
smaller than in another MD investigation, but show signals of a
conformational change upon binding, which on turn could be linked
to receptor activation. with PAF-like function, could role in the
clinical manifestation of FMS. New disease biomarkers and
therapeutic targets in Fibromyalgia; aid to design new diagnostic
& therapeutic approaches & diets.
