Molecular graphics and

modeling
Dr. Ravi Kiran Purama

Molecular graphics and modeling

Constructing an Initial Model
There are two distinct methods for generating an initial model of a molecular system for a
molecular modeling study.
The model can either be derived from existing structural information held in databases or the
chemical intelligence of the user and the molecular modeling system can be used to generate
a model within the system.
A wide variety of techniques are available for generating an initial model.
These include:
entering a 1-D notation (such as SMILES) from which a rule-based or distance geometry-based
approach can generate a 3-D structure.
sketching in 2-D a diagram of the structure either generated free hand or by connecting
fragments. The main requirements of the software are to maintain chirality, valency, or
aromaticity as appropriate, to allow assignment of charge, generate an acceptable 3-D
structure, and often assign atom types and parameters for force-field calculations.
building/editing in 3-D, in a way similar to the 2-D case; this can be sketching the molecule
in 3-D or connecting together appropriate 3-D fragments to construct a molecule, with the
addition of automatic refinement of bond distance, angles, and dihedrals as the building
continues.

Molecular graphics and modeling

Constructing an Initial Model
The second main category of techniques for generating an initial model is to search
databases of known molecules related to the molecule under consideration and to
generate an initial model from this.
A wide range of databases need to be considered. There are databases of known
experimentally determined structures such as the Brookhaven Data Bank for proteins
(Bernstein et al., 1977) and the Cambridge Crystallographic Data Centre's database
for small molecule crystal structures (Allen et al., 1979).
The number of structures in these databases continues to grow at an impressive
rate. These have been augmented by a number of small molecule databases in
which the chemical information has been extended to a 3-D structure using
techniques such as CONCORD.
Examples here include the CAST 3-D database (available from Chemical Abstracts),
the Available Chemicals Directory (available from MDL), the Maybridge directory of
pharmaceuticals, or inhouse proprietary databases. The main requirements are large
amounts of disk space to hold these databases, a flexible query language to allow
searches to be defined in a natural way, and a browsing facility to help characterize
the results of the search.

Molecular graphics and modeling

Refining the Model
Once an initial model of the molecular system has been constructed, it
is necessary to explore the conformations available to the molecule.
Sometimes it is the lowest energy structure of a molecule that is of
interest. In other cases, the range of conformations available are
necessary to represent the structure.
In theory, quantum mechanical calculations should provide a complete
description of the energy of any particular conformation of a
molecule. In practice this is not possible because of the number of
atoms involved (and thus wave functions) and because of the
inaccuracies from the approximations that must be made. For this
reason, molecular mechanics is the main technique used to evaluate
the energy of a molecule and from this search for the preferred
conformations.

Molecular graphics and modeling

Refining the Model
Molecular mechanics is essentially an approach to calculating the
energy of a molecule using an empirical energy function which
attempts to describe covalent bonds in terms of "springs" connecting
atoms with van der Waals and electrostatic interactions between
nonbonded atoms. A number of potential functions have been
developed for use with polyatomic systems. In most of these a bond is
described as a harmonic restoring force with penalties for deforming
bond angles, a dihedral torsional potential to allow for hindered
rotations of groups about a bond, and nonbonded interactions between
separated atoms.
An expression of the following form is the most widely used and is the
basis of many of the force fields widely in use. Some have additional
terms defining additional interactions or constraints between groups of
atoms.

Molecular graphics and modeling

force fields calculation

Molecular graphics and modeling

where the first term represents the covalent bond interaction (b)
and the second term is for bond angles (). Two terms are used
for the dihedral angle: a harmonic term for torsions () that do
not undergo transitions (e.g., dihedral angles within aromatic
rings) and a sinusoidal term for the other dihedral angles ().
The two terms that result from the interaction of pairs of atoms
involve the Lennard-Jones (6-12) interaction and the coulombic
effect between charge atoms. C12 and C6 are constants for a
particular atom pair interaction, and 0 and r are the vacuum
and relative permitivity, respectively.

Molecular graphics and modeling

In energy minimization, the coordinates of the system are changed so as to minimize the
total energy of the system.
Because of the number of degrees of freedom and the multiple minima nature of the
potential energy surface, it is not possible to find the conformation corresponding to the
global energy minimum except for quite small molecules.
Generally, energy minimization finds a local minima close to the starting structure. In
conformational analysis, the conformation of the molecule is varied while monitoring the
energy of the system.
If there are a limited number of flexible bonds in the molecule, then an exhaustive search of
all possible conformations can be made. For more than about five to six bonds, then various
strategies have to be adopted to make the search of conformational space more tractable.
These include random generation of conformations and techniques such as Boltzmann Jump.
The latter is a form of Monte Carlo sampling in which changes to the structure are always
accepted if they result in a reduction in energy and with a Boltzmann probability if the
energy of the system has increased. From these techniques a set of conformations can be
achieved.
Because conformational analysis usually works with a fairly coarse grid of dihedral angles
(~10-30) each step is usually followed by minimization to find the locally best structure.

Molecular graphics and modeling

Another technique used to explore the conformational space of molecules is
molecular dynamics. The basic feature of molecular dynamics is the calculation of a
trajectory of the molecule, i.e., a series of structures in which the system is moving
under the influence of the forces acting on the atoms.
These are calculated from the first derivative of the potential function with respect
to the atom positions.
By applying Newton's equations of motion, these forces can be used to calculate how
the atomic positions change with time, giving rise to a dynamics trajectory, a series of
conformations for the molecule which evolves with time.
The general strategy is to calculate the forces on the atoms in the system and then
allow the atoms to move under influence of this force, usually for a femtosecond.
New forces are then calculated from these positions to be applied in the next step of
dynamics and so on. In some methods, extra forces are considered to simulate the
presence of solvent or some external heat bath (Langevin dynamics). A critical aspect
of using potential energy functions is providing appropriate parameters for the system
under study. Many different parameter sets have been developed for a variety of
different force fields. It is always important to check that the parameters and force
field that are being used have been validated for the particular molecular system
under study.

Molecular graphics and modeling

Manipulating the Model
The essence of an interactive molecular modeling system is the ability for the
scientist to explore the conformational variability and properties of molecules and
how they may interact with each other.
Sometimes these relationships can be explored automatically using algorithms based
on the empirical force field conformational search techniques discussed earlier. In
most molecular modeling systems, however, there is a need for some basic modeling
tools, such as:
moving molecules or fragments of molecules about relative to each other while
monitoring bad contacts or energy of interaction (favored)
specification of flexible bonds and rotating around these torsion angles with
monitoring of contacts and energy
solid docking procedures which prevent the manual modeling from moving the
molecules so close to each other that they penetrate
semiautomated docking procedures (such as least-squares fitting or distance
geometry) which suggest ways in which two molecules can satisfy certain
restraints.

Molecular graphics and modeling

Visualization
the different techniques available for display of molecular structure
and properties
The simplest and by far the most widely used graphical method for
representing molecular structure and properties is vector graphics
where the bonds in the molecules are represented as lines joining the
atoms
An important feature is the ability to rotate, scale, and translate with
full three dimensional clipping and depth cueing
interactive vector graphics a very powerful tool for studying
molecules; the representation of the bonds within a molecule as
vectors not only reveals the essential chemistry of the molecule but
also allows the complete detail of the structure to be appreciated

Molecular graphics and modeling

Difficult to see the depth
Progressively Darker

Molecular graphics and modeling

Raster Graphics - allow more detailed representations of the structure to be rendered in real
time
ball and stick representation in which the atoms are drawn as shaded spheres of varying
radius to reflect the element type, connected by cylinders
When the radius of the atoms is uniform and the same as the radius of the bond cylinders,
then the licorice representation

Molecular graphics and modeling

Shaded spheres at van der Waals radius give the impression of the overall
shape and packing of the atoms in the molecule, but the details of the
chemical structure are difficult to discern.
type of representation is only useful in showing the overall organization of
the molecule, such as in the distribution of polar atoms over a molecular
surface, or in showing the packing together of molecules in a complex.

Connolly (Langridge et
al., 1981) in which the
molecular surface is
defined by the surface in
contact with a probe
sphere as the sphere
"rolls" over the surface
of the molecule.
A l t e r n a t i v e l y, t h e
extended solvent
accessible surface can
be calculated in which
the surface is traced out
by the center of the
probe sphere as it rolls
over the molecule.
shows the molecular
surface for our peptide
molecule

Molecular graphics and modeling

An alternative representation of the surface with similar properties is the production of a molecular envelope as a
contoured grid of lines
the three-dimensional grid of electron density values were contoured in three dimensions to produce the chicken-wire
representations of density
Fig. 13, this is a simple calculation in which a three-dimensional grid was placed over the molecule and the grid points
were assigned a value related to their distance from an atom. Contouring this produces a molecular surface.
Raster Fig. 14. by triangulating the dots produced in the Connolly surface.

Molecular graphics and modeling

ray tracing which can give added realism to a graphics image by calculating shadows and
complex lighting and shading.
The main advantage is the increased three dimensional perception from the casting of
shadows.

Molecular graphics and modeling

color is a vital component of any molecular visualization.
Color is extremely important for two main areas
The first is to aid in the presentation and interpretation of
complex and large molecules
the atoms could be colored on element type or atomic charge to
highlight the chemistry of the molecule or different parts of the
system could, be colored to illustrate packing in a complex
Second, color can be used on molecular surfaces or other
representations to highlight the properties of the molecule, such
as electrostatic potential or hydrophobicity