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Unraveling the mechanism of CETP inhibition through Molecular Dynamics simulations: Insights for rational drug discovery Revathi.S BT12S020.

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Presentation on theme: "Unraveling the mechanism of CETP inhibition through Molecular Dynamics simulations: Insights for rational drug discovery Revathi.S BT12S020."— Presentation transcript:

1 Unraveling the mechanism of CETP inhibition through Molecular Dynamics simulations: Insights for rational drug discovery Revathi.S BT12S020

2 Introduction

3 Coronary artery diseases and CETP Atherosclerosis - leading cause of mortality in industrialized nations. Recent studies have shown that Cholesteryl Ester Transfer Protein (CETP), which modulates the neutral lipid profile in the body between HDL and LDL, is an effective target. Koivuniemi, A., T. Vuorela, et al. (2012). PLoS Computational Biology 8(1).

4 Cholesteryl ester transfer protein Boomerang shaped protein molecule with a hydrophobic tunnel. Transfers lipids between High Density Lipoprotein (HDL) and Low Density Lipoprotein (LDL) Inhibiting CETP caused reduction of plaques in the arterial walls of rabbits. Qiu, X., A. Mistry, et al. (2007) Nature structural & molecular biology 14(2): Zhang, L., F. Yan, et al. (2012) Nature chemical biology 8(4):

5 Currently available inhibitors of CETP Objective To study the mechanism of CETP inhibition by the 3,5-bis(trifluoromethy)phenyl derivatives

6 Methodology

7 Molecular dynamics Simulations Biomolecular simulations – Computational microscope for molecular biology. Molecular Dynamics is based on Newtons laws of motion Computer Simulations of Liquids Allen and Tilldeseley -E=F i Bonded Non-bonded

8 Why do we need HPCE for MD? System under study: – Protein of 7500 atoms protein – 522 lipid atoms – 81 atoms of inhibitor (variable) – 268 Na Cl - ions – atoms from water – Total of over atoms

9 Software used: NAMD2.9 System scales up to 11ns/day with 256 CPUs in VIRGO

10 Flow Chart Ligand structure optimization by Gaussian 3.0 Docking of the inhibitors to CETP by AutoDock4 Molecular Dynamics Simulations by NAMD2.9 with CHARMM36 forcefield Visualization and Analysis using VMD1.9.1 and GROMACS

11 RMSD as a function of time reveals that the systems have stabilized. RMSF results show that the N-terminal distal region of the inhibitor bound CETP has higher atomic fluctuations in comparison to the substrate-bound complex. Results

12 Dynamic Cross Correlation Analysis Substrate bound CETP Torcetrapib bound CETP Anacetrapib bound CETP Evacetrapib bound CETP Inhibitor binding increases the anti-correlation between the binding site and distal regions of CETP Anti-correlation Positive -correlation Grant, Rodrigues, ElSawy, McCammon, Caves, (2006) Bioinformatics 22,

13 Principal Component Analysis The above plot reveals that the first 20 Eigen vectors are required to describe 80% of the overall dynamics of the protein. Pronk, S., S. Páll, et al. (2013). Bioinformatics (Oxford, England) 29(7): Inhibitor bound complexes are more dynamic than the substrate bound complex

14 Protein Dynamics from PCA : PC1

15 Protein Dynamics from PCA : PC2

16 PCA : Porcupine plots PC1PC2 Substrate bound Inhibitor bound Inhibitor bound CETP shows greater extent of twisting in PC2 Humphrey, W., Dalke, A. and Schulten, K., "VMD - Visual Molecular Dynamics", J. Molec. Graphics, 1996, vol. 14, pp

17 APBS Analysis The N-terminal distal region of both the complexes become predominantly electropositive over time. The inhibitor bound complex becomes relatively more electropositive. 0 ns50 ns 100 ns150 ns Baker NA, Sept D, Joseph S, Holst MJ, McCammon JA. Electrostatics of nanosystems: application to microtubules and the ribosome. Proc. Natl. Acad. Sci. USA 98, Substrate-bound Torcetrapib-bound Anacetrapib-bound Evacetrapib-bound

18 In conclusion.. Inhibitor binding affects the atomic fluctuations at the distal regions of CETP. Inhibitor binding increases the anti-correlation between the binding site and distal regions of CETP. PCA reveals increased dynamics of the inhibitor bound complexes. Dynamic Cross Correlation Analysis and PCA are indicative of differential twists in the inhibitor-bound systems. This twisting results in the progressive exposure of electropositive residues in the N-terminal distal region. Improved electro-positivity at the HDL –sensing N-terminus supports the existing hypothesis of high affinity of inhibitor bound complexes towards HDL having electronegative surface thereby resulting in the formation of non-productive CETP-HDL complex.* *Clark RW, Ruggeri RB, Cunningham D, Bamberger MJ J Lipid Res 2006;47:537–552

19 ACKNOWLEDGEMENTS Principal Investigator : Dr.Sanjib Senapati Members of the Computational Biophysics Lab, IITM HPCE Team: Mr. V. Ravichandran Mrs.P.Gayathri THANK YOU…


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