14. Why can’t theory help? The underlying physical laws necessary for the mathematical theory of a large part of physics and the whole of chemistry are thus completely known, and the difficulty is only that the exact application of these laws leads to equations much too complicated to be soluble. P. A. M. Dirac, Proc. R. Soc. London 123, 714 (1929) This is no longer true, computers can solve the equations. Given 10^12 years. Confidential and Proprietary
20. QUANTUM MECHANICAL POLARIZABLEFORCE FIELD (QMPFF) All major current force fields including AMBER and Merck Molecular Force Field (MMFF) are based on similar principles that date back decades ago QMPFF is designed to be physically more realistic and therefore more accurate by fully integrating quantum physics – made possible by vast increases in computer speed to do necessary calculations
21. +1 +1 QMPFF CONCEPT Conventional Molecular Representation QMPFF Molecular Representation H2O H2O + 0.4 - 0.45 - 7.1 +6 - 0.8 - 0.45 + 0.4 Point charges known to be physically unrealistic; no natural way to include important polarization energy term Charge clouds approximate quantum reality; polarization naturally introduced via shifting of electron clouds
22. QMPFF technology captures the missing details Quantum Mechanical Polarizable Force Field (QMPFF) Polarizable force field models polar interactions (see below) Can model water, gas phase, ligand binding better than any existing computational tools using the same parameters. Produced Dipole Electric Field + Confidential and Proprietary
23. Interacting entities are cloud-like, polarizable O Parameterized from QM calculations. Polarizability is essential to modeling biological interactions. Electron clouds adjust during the simulation-> (real VdW). + - - - + + H H Confidential and Proprietary
26. QMPFF AND DRUG DESIGN QMPFF via MD simulation can be applied to calculate relative binding free energy (and therefore relative binding affinity) of two related ligands for a protein X-ray structure of protein is required, and structure of complex with representative ligand(s) is very helpful
27. We mutate one ligand into another Thermodynamic integration Each alchemical mutation requires running a series of simulations. Takes approximately 8 days per calculation (10 cores). Most suitable for lead and drug optimization. Mutation Confidential and Proprietary
28. 2BZA benzyl-ammonium BINDING FREE ENERGY CALCULATIONS FOR 1TNH AND 2BZA IN TRYPSIN 1TNH 4-fluoro-benzyl-ammonium ΔΔG (kcal/mol) QMPFF3 0.85 0.17 MMFF94 -0.4 Exper. 0.78
29. Does it work? Ligand substitution pilot study (trypsin, thrombin and uPA inhibitor families). Nothing else can predict free energies accurately (see comparison to Merck results below) QMPFF MMFF Confidential and Proprietary Actual