Molecular Modeling: Molecular Mechanics

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

2. Guidelines for Use • What systems were used to parameterize • How is energy calculated • What assumptions are used in the force field • How has it performed in the past

3. Transferability • AMBER (Assisted Model Building Energy Refinement) • Specific to proteins and nucleic acids • CHARMM (Chemistry at Harvard Macromolecular Mechanics) • Specific to proteins and nucleic acids • Widely used to model solvent effects • Molecular dynamics integrator

4. Transferability • MM? – (Allinger et. al.) • Organic molecules • MMFF (Merck Molecular Force Field) • Organic molecules • Molecular Dynamics • Tripos/SYBYL • Organic and bio-organic molecules

5. Transferability • UFF (Universal Force Field) • Parameters for all elements • Inorganic systems • YETI • Parameterized to model non-bonded interactions • Docking (AmberYETI)

6. How is Energy Calculated • Valence Terms • Cross Terms • Non-bonding Terms • Induced Dipole-Induced Dipole • Electrostatic/Ionic (Permanent Dipole) System not far from equilibrium geometry (harmonic) • Energy is ? • Strain Energy (E=0 at equilibrium bond length/angle) • Field Energy (Energy due to Non-bonding terms) • Atomistic Heats of Formation (Parameterized so as to yield chemically meaningful values for thermodynamics) • K. Gilbert: This is only in the MM?-type force fields

7. Assumptions • Hydrogens often not explicitly included (intrinsic hydrogen methods) • “Methyl carbon” equated with 1 C and 3 Hs • System not far from equilibrium geometry (harmonic) • Solvent is vacuum or simple dielectric

8. Modeling Potential energy

9. 0 0 at minimum Modeling Potential energy

10. Assumptions:Harmonic Approximation

11. Assumptions:Harmonic Approximation Determining k?

12. Assumptions:Harmonic Approximation E(.65)=3.22E-20J E(.83)=2.13E-20J Dx=.091

13. Assumptions:Harmonic Approximation

14. Assumptions:Harmonic Approximation

15. Assumptions • Hydrogens often not explicitly included (intrinsic hydrogen methods) • “Methyl carbon” equated with 1 C and 3 Hs • System not far from equilibrium geometry (harmonic) • Solvent is vacuum or simple dielectric

16. Assumptions:solvent effects DFT H2 in Pd Christensen, O. B. et. al, Phys. Rev. B. 40, 1993 (1989)

17. Intermolecular/atomic models • General form: • Lennard-Jones Van derWaals repulsion London Attraction

18. MMFF Energy • Electrostatics (ionic compounds) • D – Dielectric Constant • d - electrostatic buffering constant

19. MMFF Energy • Analogous to Lennard-Jones 6-12 potential • London Dispersion Forces • Van der Waals Repulsions The form for the repulsive part has no physical basis and is for computational convenience when working with largemacromolecules. K. Gilbert: Force fields like MM2 which is used for smaller organic systems will use a Buckingham potential (or expontential) which accurately reflects the chemistry/physics.

20. N >> 1000 atoms Easily constructed Accuracy Not robust enough to describe subtle chemical effects Hydrophobicity Excited States Radicals Does not reproduce quantal nature Pros and Cons

21. Caveats • Compare energy differences NOT energies • Always compare results with higher order theory (ab initio) and/or experiments