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Computational Chemistry and Molecular Modeling Lecture 1 08.2.12 CH418 computational Chemistry KAIST COMPUTATIONAL CHEMISTRY (Use computers to solve chemical problems) Computation | Theory | Modeling Simulation QUANTUM CHEMISTRY (Quantum mechanics + Chemistry)

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computational chemistry and molecular modeling

Computational Chemistry and Molecular Modeling

Lecture 1 08.2.12CH418 computational Chemistry




(Use computers to solve chemical problems)








(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)


Molecular modeling starts from structure determination

Selection of calculation methods in comp chem

Starting geometry from

standard geometry, x-ray, etc.


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


Is solvation







dynamics or

Monte Carlo

in practice computation theory modeling are interchangeable and can be regarded as simulations
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 Ponder’s web page

(more relevant to biomolecules and TINKER)


Classification of computational biologist

- all are simulations for this course

why do we perform simulations especially for biological molecules
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
advantage of simulations
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
connection to conventional wet lab experiments
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


􀂃 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

disadvantages of simulations
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


  • Some distinguish QM calculations from simulations
what makes simulations of biological systems possible
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


• 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)

how do we perform simulations
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

what do we simulate
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 can’t afford to simulate everything

how do we perform simulations16
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 it’s an experiment)

• We use exotic principles such as

􀂃 Newton’s laws – kinematics

􀂃 Coulomb’s law – electrostatics

􀂃 Fluid dynamics

􀂃 Polymer dynamics

􀂃 Schrödinger equation

simulation technology
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

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