1. Molecular Modeling: Molecular Mechanics C372 Introduction to Cheminformatics II Kelsey Forsythe

2. Review Energy components Energy components Guidelines for use Guidelines for use Pros and Cons Pros and Cons Geometry optimization Geometry optimization

3. Today Modeling inorganic systems Modeling inorganic systems Modeling macromolecules Modeling macromolecules Ligand-receptor interactions Ligand-receptor interactions Beyond Empirical Methods Beyond Empirical Methods Ab Initio Ab Initio Semi-Empirical Semi-Empirical

4. Comparison of Empirical Models Copy of p.443 from Gundertofte article Copy of p.443 from Gundertofte article See also Cramer Table 2.1 See also Cramer Table 2.1

5. Hypervalent Systems SF 6 SF 6 MMFF MMFF r(SF) = 1.633A (EXPT = 1.564A) r(SF) = 1.633A (EXPT = 1.564A) SYBYL SYBYL r(SF) = 1.800A (EXPT = 1.564A) r(SF) = 1.800A (EXPT = 1.564A)

6. One Atom Heavy Hydrides MMFF MMFF r(NH 3 ) = 1.019A (EXPT = 1.012A) r(NH 3 ) = 1.019A (EXPT = 1.012A) SYBYL SYBYL r(NH 3 ) = 1.080A (EXPT = 1.012A) r(NH 3 ) = 1.080A (EXPT = 1.012A) Mean error (bond distances): Mean error (bond distances): SYBYL -.262 SYBYL -.262 MMFF -.026 (Comparable to small basis Hartree-Fock) MMFF -.026 (Comparable to small basis Hartree-Fock) Similar performance for multiple heavy atom hydrides Similar performance for multiple heavy atom hydrides Hehre, W. J., A Guide to Molecular Mechanics and Quantum Chemical Calculations

7. Multiple Heavy Atom Systems ~150 compounds ~150 compounds Benzene, difluromethane, tetrachlorosilane, ozone, magnesium fluoride Benzene, difluromethane, tetrachlorosilane, ozone, magnesium fluoride Mean error (bond distances): Mean error (bond distances): SYBYL -.051 SYBYL -.051 MMFF -.034 MMFF -.034 Ab initio (HF) -.028 Ab initio (HF) -.028

8. Transition Metal Molecules MMFF and SYBYL NOT parameterized MMFF and SYBYL NOT parameterized MMX - some parameterization for inorganics MMX - some parameterization for inorganics UFF - parameters for all elements UFF - parameters for all elements MOMEC MOMEC VALBOND VALBOND

9. Modeling macromolecules Solvent-Solute (i.e. Non-Bonding) interactions very important Solvent-Solute (i.e. Non-Bonding) interactions very important Ligand-Receptor interactions Ligand-Receptor interactions Protein Folding Protein Folding Dreiding Dreiding AMBER (protein structure) AMBER (protein structure) OPLS OPLS Chem-X Chem-X CHARMM (“ “) CHARMM (“ “) YETI (ligand-protein) YETI (ligand-protein) CFF (proteins) CFF (proteins) MMFF (hydrogen-bonding) MMFF (hydrogen-bonding) Tripos/SYBYL Tripos/SYBYL

10. MMFF Parameterized to Ab Initio Parameterized to Ab Initio Non-Bonding Interactions Non-Bonding Interactions Hydrogen bonding Hydrogen bonding Water n-mers Water n-mers Non-polar (vdW) Non-polar (vdW) (H 2 ) 2, (CH 4 ) 2 (H 2 ) 2, (CH 4 ) 2

11. Macromolecular Modeling D-glucose - 11 different conformers D-glucose - 11 different conformers GROMOS, MM3 GROMOS, MM3 1.5-2.1 kcal/mol 1.5-2.1 kcal/mol CHARMM, MMFF CHARMM, MMFF 0.9-1.5 kcal/mol 0.9-1.5 kcal/mol AMBER, Chem-X, OPLS AMBER, Chem-X, OPLS 0.6-0.8 kcal/mol 0.6-0.8 kcal/mol Barrows, S. E. et al, 1998. J. Comput. Chem. 19, 1111.