Computational Chemistry and Molecular Modeling

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Computational Chemistry and Molecular Modeling

• Lecture 1 08.2.12CH418 computational Chemistry
• KAIST

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COMPUTATIONAL CHEMISTRY (Use computers to solve
chemical problems)
Computation Theory Modeling Simulation
QUANTUM CHEMISTRY (Quantum mechanics Chemistry)
Molecular Modeling (mimic molecular behavior
with models)
The underlying physical laws necessary for the
mathematical theory of a large part of physics
and the whole of chemistry are thus completely
known, and the difficulty is only that the exact
application of these laws leads to equations much
too complicated to be soluble. P.A.M. Dirac
1902-1984 Proc. Roy. Soc(London) 123,
714(1929)
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Molecular modeling starts from structure
determination Selection of calculation methods in
comp chem
Starting geometry from standard geometry,
x-ray, etc.
Molecule
Is bond formation or breaking important? Are
many force field parameters missing? Is it
smaller than ca. 100 atoms? Are charges of
interest?
Are there many closely spaced conformers? Is
plenty of computer time available? Is the free
energy needed? Is solvation important?
Molecular mechanics
Quantum mechanics
Molecular dynamics or Monte Carlo
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In practice, Computation, Theory, Modeling are
interchangeable and can be regarded as simulations

• Why do we perform simulations?
• What makes simulations possible?
• How do we perform simulations?
• What types of things/systems do we simulate?
• Engineering aspects of simulations

This and following slides are from Ponders web
page (more relevant to biomolecules and TINKER)
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Classification of computational biologist - all
are simulations for this course
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Why do we perform simulations (especially for
biological molecules) ?

• Simulations are experiments performed on a
  computer
• (Repeat) Simulations are experiments performed on
  a computer
• Simulations represent a controlled environment
• Probe length and time scales not accessible by
  other means

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Advantage of simulations

• Simulations are not limited by the laws of
• physics we define the laws and basis of
• interaction, dynamics, etc. whether they be
• physical or nonphysical
• ?? Ignore forces gravity, viscosity
• ?? Use of simple, effective potentials that give
  the
• correct dynamics (simple harmonic oscillator)
• ?? Increase time rate slow reactions, diffusion
• limited reactions
• ?? Sampling explore interesting regions of
  phase
• space that may only be periodically visited

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Connection to conventional wet Lab experiments

• - Confirm, extrapolate and predict wet lab
  experimental
• results simulations represent just one more
• experimental tool, just like EM, AFM, Stopped
  Flow,
• Can be cheaper, faster and easier than wet-lab
• experiments
• ?? No protein expression, purification,
• ?? Mutations, combinatorial chemistry, etc. is
  now easy
• ?? Drug libraries high throughput screening
• Provides details not available in typical
  experiment
• ?? Single molecule dynamics like laser tweezers
• ?? Reaction pathways
• ?? Atomic/ Molecular level dynamics similar to
  neutron scattering or NMR

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Ponder ChemBio Lecture note
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Disadvantages of simulations

• - A simulations is only as realistic as you
• make it since you control the physics,
• the physics must be correct
• Can be time consuming and approximate
• Does not have wide based support from
• the experimental community (changing
• slowly)
• Some distinguish QM calculations from simulations

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What makes simulations (of biological systems)
possible ?

• - All sciences are based primarily on numbers,
  except for
• biology this has started to change in the past
  few
• decades.
• Simulations have become possible since
  biological
• information is able to be expressed as data
  useful for
• computing (discrete objects)
• Protein sequence and structures
• ?? Sequence information (genome, protein)
• ?? Fold types
• ?? Secondary structure elements (alpha helices,
  beta sheets, )
• ?? Tertiary structure (structure of folded
  protein)
• ?? Quaternary structures (filaments, polymers)

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How do we perform simulations?

• Simulation does not mean programming! Most
• simulations techniques, methods, programs,
  algorithms
• exist in the public domain. Experimentalists can
  and do
• perform good simulations.
• Simulations tend to produce lots of data and
  not just one
• simple answer. You must understand in detail the
• physics of a system in order to design a
  simulation, and
• you must understand just as much in order to
  interpret
• the results.
• Simulations can be serial or parallel. Today,
  most
• people use PCs for serial jobs and Beowulf
  clusters or
• supercomputers for parallel applications

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What do we simulate?

• - Historically, simulations were very simple
• molecules were spheres, no solvent, now we
• can simulate as much detail as we want (if we
• are willing to pay the price)
• Now, we are starting to simulate large
• biomolecular and nano systems, but challenges
  still exist
• All simulations present a challenge to balance
• the detail of a simulation with the length of
  time it
• takes to run we cant afford to simulate
  everything

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How do we perform simulations?

• -This is not theoretical work (most times) since
• we are not proposing new physical laws or
• interactions. All we are trying to do is recreate
• or mimic the physical environment and the
• interactions between the molecules/proteins
• involved (remember its an experiment)
• We use exotic principles such as
• ?? Newtons laws kinematics
• ?? Coulombs law electrostatics
• ?? Fluid dynamics
• ?? Polymer dynamics
• ?? Schrödinger equation

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Simulation technology

• - Increase in computational speed has come at
• the same time as the biological information
• Computer Simulations will be required !!
• ?? Too time consuming and costly to get
  structures for all
• the proteins the protein folding problem will
  have to
• be solved.
• ?? Once we get protein structures, we need to be
  able to
• figure out the physical basis for their
  interaction in
• order to understand protein complexes

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Locating critical points on the potential energy
surface(PES) is the major task of molecular
simulations

• PES collection of energy values at the given
  arrangement of atoms
• Quantum mechanics
• Works with nuclei and electrons
• Quantum chemical methods
• Classical mechanics (molecular mechanics)
• Works with atoms bonded or nonbonded
• Usually connection between atoms predefined

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H/W and S/W issues