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Molecular Modeling: Molecular Mechanics

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

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Molecular Modeling: Molecular Mechanics

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  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

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