DNA Technology in the New Millennium

1
DNA Technology in the New Millennium

• Molecular Modeling and Drug Discovery Techniques
• Summer 2002
• Dr. Joseph Smith
• Science Department
• Cabrini College

2
Todays Session

• review some background on computational methods
• examples of some simple calculations on a small
  molecule
• examples of some simple calculations on peptides
  and nucleic acids

3
Spartan Software

• Developed by Wavefunction, Inc.
• 18401 Von Karmon, Suite 370
• Irvine, CA 92612
• www.wavefun.com
• sales_at_wavefun.com

4
Value of Computational Techniques in Drug
Discovery

• allows prediction and understanding of molecular
  properties and chemical behavior
• allows understanding of structureactivity
  relationships (SARs)
• allows insight into potential drug candidates

5
Computerized Calculations

• power of contemporary chips allows for high speed
  calculations on molecules in a reasonable amount
  of time
• graphical user interface allows for easy
  construction of molecules and convenient
  visualization of molecular properties such as
• -molecular structure
• -electric dipole moment
• -charge distribution
• -highest occupied molecular orbitals (HOMOs)
• -lowest unoccupied molecular orbitals (LUMOs)
• -electron density maps

6
Types of Calculations

• I) Methods based on Classical Mechanics
• (aka molecular mechanics or force field
• methods)
• ex. MMFF, SYBYL, MM2, MM3
• simple and fast
• treats a molecule as a collection of balls
  (atoms) and springs (bonds)
• good for small and large molecules

7
Types of Calculations

• II) Methods based on Quantum Mechanics
• three theoretical models
• 1) semi-empirical, ex. AM1, PM3, MNDO
• 2) ab initio, ex. Hartree-Fock, MP2, MCSCF
• 3) density functional theory, ex. SVWN, BP
• all three models are used to approximate solution
  to Schrodinger equation
• HYEY
• complex and require longer calculation times
• restricted to small molecules

8
Molecular Mechanics Calculations

• Minimizes energy of molecule relative to strain
• energy associated with
• 1) bond length
• 2) bond angle
• 3) torsion angle
• 4) van der Waals interactions
• 5) electrostatic interactions
• 6) other interactions depending on method

9
Molecular Mechanics Calculations

• For a given structure, energy minimization
  explores potential energy surface and results in
  lowest energy conformation (local energy minimum)
• The resulting optimized geometry manifests the
  least strain possible (bond, angle, torsion, van
  der Waals, electroctatic, etc.)
• A different calculation (ex. Monte Carlo
  simulation) is required to guarantee that local
  minimum is also the global minimum

10
Approach Used in Molecular Modeling

• 1) identify problem
• 2) build molecule
• 3) run calculation (energy minimization)
• 4) interpret results