Coarse-grained molecular dynamics simulations of High Density Lipoprotein (HDL)

1. Venkat Reddy Chirasani Laboratory of Computational Biophysics Coarse-grained molecular dynamics simulations of High Density Lipoprotein (HDL) HPC Symposium 2014

2. LIPOPROTEINS: • Lipoproteins are macromolecular aggregates of lipids and proteins that function to transport otherwise insoluble lipid molecules through the plasma • Although different types of lipoprotein particles circulate in plasma, viz. HDL,LDL,IDL,VLDL, their structures are similar Erez scapa et al., Lipoprotein metabolism, Pg.no:133-142

3. HDL LDL Size = 50 to 120 Å Density = 1.063 to 1.21 g/ml No. of lipids = 90 - 400 VLDL Size = 180 to 280 Å Density = 1.02 to 1.063 g/ml No. of lipids = 2500 - 3000 Size = 300 to 900 Å Density = 0.93 to 1.006 g/ml No. of lipids = ~4000 Ilpo et al., PLoSComputBiol, 2010

4. High Density lipoprotein (HDL) • HDL transports excess cholesterol from arteries to liver for excretion and prevents the progression of atherosclerosis. • Main lipid constituents of HDL are - Phospholipids (POPC+PPC) - Cholesteryl Esters (CE) - Triglycerides (TG) - Free Cholesterol (CHOL) • HDL is wrapped majorly by apoA-I which facilitates the esterfication of cholesterol. Glass CK and Witztum JL, Cell ,104:503-516

5. Progression of Atherosclerosis Libby P, Circulation, 104:364-372 (2001)

6. Despite the importance of HDL in atheroprotection, very less • is known about its structure. • Detailed information on structural organization of HDL would • help in studying its interactions with other proteins (CETP). • The knowledge about HDL structure would further help in • understanding the lipid transfer mechanism between • lipoproteins.

7. Why Coarse-grained simulations? • The time scale of lipid mixing is of the order of 1 μs • (derived through the diffusion of lipids inside HDL) • Its very difficult to achieve μs scale dynamics using all- • atomic simulation • Recent CG simulations of lipids and proteins have closely • reproduced the experimental data Risselada HJet al.,Proc Natl Acad Sci USA. 105: 17367–17372 (2008) Ollila OHS et al., Phys Rev Lett 102: 078101 (2009) Catte A et al., J R Soc Interface 6: 863–871 (2009)

8. Materials and Methods: • GROMACS simulation package • Coarse-Grained MARTINI force field • Pymol for apoA-1 model construction • VMD for visualization

9. Coarse grained representation of atomistic models: Ilpo et al., PLoSComputBiol, 2010

10. 10 ns Random configuration 2 μs Hydrophobic melt Spherical HDL

11. Structure of HDL and apoA-I organization: An average sized HDL is wrapped-up with four apoA-I chains Huang R et al.,Nat. Struct. Mol. Biol. 18:416–422 (2011)

12. Huang R et al.,Nat. Struct. Mol. Biol. 18:416–422 (2011)

13. Modeling of tetrafoilapoA-I bound HDL: 300 1200 There were 31 inter-chain salt bridges in the tetrafoilapoA-1 model to stabilize the apoA-1 organization on HDL

14. Analysis:

15. Diffusivity (D): • The large scale dynamics within HDL are measured by diffusion • coefficient D. • The diffusion coefficients were determined by considering lipid • displacement distribution function over a fixed period of time.

16. Annular lipids: The lipid beads that are with in 8Å from any protein bead of apoA-1 are known as annular lipids. Ilpo et al., PLoSComputBiol, 2010

17. The average radius of HDL with apoA-1 over 12us is 5.36nm

18. apoA-I analysis: Ilpo et al., PLoSComputBiol, 2010

19. Conclusion: • An insilicohigh resolution HDL model with tetrafoilapoA-I was built. • The model is accurate in terms of experimental and theoretical physiological parameters. • The HDL model can be used to study the lipid transfer mechanism.

20. GROMACS benchmark ns/day