Molecular modeling molecular mechanics
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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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Molecular modeling molecular mechanics

Molecular Modeling:Molecular Mechanics

C372

Introduction to Cheminformatics II

Kelsey Forsythe


Guidelines for use

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

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


Transferability1

Transferability

  • MM? – (Allinger et. al.)

    • Organic molecules

  • MMFF (Merck Molecular Force Field)

    • Organic molecules

    • Molecular Dynamics

  • Tripos/SYBYL

    • Organic and bio-organic molecules


Transferability2

Transferability

  • UFF (Universal Force Field)

    • Parameters for all elements

    • Inorganic systems

  • YETI

    • Parameterized to model non-bonded interactions

    • Docking (AmberYETI)


How is energy calculated

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


Assumptions

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


Modeling potential energy

Modeling Potential energy


Modeling potential energy1

0

0 at minimum

Modeling Potential energy


Assumptions harmonic approximation

Assumptions:Harmonic Approximation


Assumptions harmonic approximation1

Assumptions:Harmonic Approximation

Determining k?


Assumptions harmonic approximation2

Assumptions:Harmonic Approximation

E(.65)=3.22E-20J

E(.83)=2.13E-20J

Dx=.091


Assumptions harmonic approximation3

Assumptions:Harmonic Approximation


Assumptions harmonic approximation4

Assumptions:Harmonic Approximation


Assumptions1

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


Assumptions solvent effects

Assumptions:solvent effects

DFT

H2 in Pd

Christensen, O. B. et. al, Phys. Rev. B. 40, 1993 (1989)


Intermolecular atomic models

Intermolecular/atomic models

  • General form:

  • Lennard-Jones

Van derWaals repulsion

London Attraction


Mmff energy

MMFF Energy

  • Electrostatics (ionic compounds)

    • D – Dielectric Constant

    • d - electrostatic buffering constant


Mmff energy1

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.


Pros and cons

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


Caveats

Caveats

  • Compare energy differences NOT energies

  • Always compare results with higher order theory (ab initio) and/or experiments


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