EUGM 2013 - Odon Farkas (Eotvos University) - Conformation search via cool dynamics
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The document discusses the differences between regular and cool dynamics in molecular simulations, highlighting significant disparities in potential energy calculations. It introduces a new conformation plugin for discovering conformers of lorazepam, utilizing various optimization techniques and comparisons with existing tools like RDKit. The findings emphasize the importance of accounting for molecular flexibility in conformational searches.
EUGM 2013 - Odon Farkas (Eotvos University) - Conformation search via cool dynamics
- 1. Conformation Search via Cool Dynamics Ödön Farkas
- 2. Comparison of Regular vs. Cool Dynamics
- 3. Comparison of Regular vs. Cool Dynamics Comparison of Regular vs. Cool Dynamics
- 4. Comparision of Regular vs. Cool Dynamics Comparison of Regular vs. Cool Dynamics
- 5. Comparison of Regular vs. Cool Dynamics The distorted structures in regular dynamics, lead to large difference in potential energies: Regular: 578 kcal/mol Cool: 35 kcal/mol
- 6. Arguments against constrained dynamics 0 50 100 150 200 250 300 350 400 -10 0 10 20 30 40 50 60 Relative potential energy curve for relaxed and rigid phenyl rotation in the case of Lorazepam Rigid Relaxed Rotation / degree Relativeenergy kcal/mol
- 7. Arguments against constrained dynamics 0 50 100 150 200 250 300 350 400 -10 0 10 20 30 40 50 60 Relative potential energy curve for relaxed and rigid phenyl rotation in the case of Lorazepam Rigid Relaxed Rotation / degree Relativeenergy kcal/molConstraints in molecular dynamics change the potential energy surface
- 8. Applying new Conformation Plugin to find conformers of Lorazepam The expected 2 conformers found (left column). The additional 4 conformers are due to the flexibility of the 7 member ring, also found
- 9. • Internal coordinate projections3 ‐ The dynamics simulation remains in Cartesian coordinates ‐ Projection of the momentum ‐ Avoid redundancy via natural internals1 ‐ Fast transformations3,7 • Sparse Cholesky decomposition4,5,7 Science used in cool dynamics
- 10. • Novel tools in the new plugin ‐ Conformation selection uses generalized Structure Stream interface ‐ Topology-aware selection ‐ Optional optimization7 for conformer search ‐ MMFF94 forcefield2 ‐ Cool dynamics is the default stream source New Conformation Plugin
- 11. 0 0.5 1 1.5 2 2.5 3 3.5 4 0 0.5 1 1.5 2 2.5 3 3.5 4 Conformation Plugin vs. RDKit RMSD RDKit RMSD ConformationPluginRMSD Comparison of New Conformation Plugin to RDKit in finding bioactive conformation
- 12. In situ structure-based design on the web
- 13. Acknowledgments ChemAxon's Discovery Team Timea Polgár Gábor Imre Filip Sedlak Adrián Kalászi Miklós J. Szabó
- 14. Thank you for your attention!
- 15. References 1. G. Fogarasi, X. Zhou, P. W. Taylor, and P. Pulay, J. Am. Chem. Soc., 1992, 114, 8191 2. Thomas A. Halgren Merck molecular force field. I. Basis, form, scope, parameterization, and performance of MMFF94, J. Comp. Chem.; 1996; 490-519 3. Farkas, Ö.; Schlegel, H. B.; Methods for optimizing large molecules. I An O(N2) algorithm for solving systems of linear equations for coordinate transformations in quantum chemical geometry optimization. J. Chem. Phys. 1998, 109, 7100-4. 4. B. Paizs, G. Fogarasi, and P. Pulay An efficient direct method for geometry optimization of large molecules in internal coordinates J. Chem. Phys. 1998, 109, 6571; 5. B. Paizs, J. Baker, S. Suhai and P. Pulay, Geometry Optimization of Large Biomolecules in Redundant Internal Coordinates, J. Chem. Phys. 2000 113(16), 6566. 6. P. Pulay and B. Paizs, Newtonian Molecular Dynamics In General Curvilinear Internal Coordinates, Chem. Phys. Lett., 2002, 353, 400. 7. Farkas, Ö.; Schlegel, H. B. Geometry optimization methods for modeling large molecules, Journal of Molecular Structure-Theochem 2003, 666, 31-39. 8. Jean-Paul Ebejer, Garrett M. Morris, and Charlotte M. Deane Freely Available Conformer Generation Methods: How Good Are They? J. Chem. Inf. Model., 2012, 52 (5), 1146–1158