Molecular Modelling In Drug Design Biology
Molecular Modelling is a significant part of chemistry in drug design which enables the manipulation and or simplification of the structure of a molecule in 3D by the use of computational means. This predicts functional properties of chemicals and other materials which involves specific calculations of quantum.
Examples of the properties that can be calculated include geometries such as bond lengths and bond angles. Energies such as heat of formation and activation energy can also be determined. Electronic properties such as moments, charges, ionization potential and electron affinity can also be obtained as well as spectroscopic properties such as vibrational modes and chemical shifts. It calculates the structure and energy of molecules based on nuclear motions.
A 2 dimensional drawing of the compound of interest is made by the use of a chemical drawing software. This 2D structure has to be transformed into a 3D structure to study the desired chemical properties which involves the use of quantum mechanics and molecular mechanics.
Quantum mechanics is a part of physics that accounts for energy and matter at the atomic level. It states that energy is radiated and absorbed in quanta. It represents the electrons in calculations making it possible to derive properties that are dependent on the electronic distribution. These include chemical reactions such as bond formation and/or bond breaking as wells as thermodynamic properties.
Molecular mechanics calculates the potential energy of all systems in molecular mechanics using force fields. It can be applied to molecules that are small but also to large molecules containing thousands of atoms, like biological systems.
This type of energy is described using the term "force field" which is a function that depends on the atomic positions. It gives an idea of the forces that are present within the molecule and is used to calculate the energy and geometry of a molecule. It takes into account the different types of atoms and parameters for bond lengths, bond angles, torsion angles and equations to calculate the energy of a molecule.
It is assumed that electrons find their optimum distribution as soon as the positions of the nuclei are known and therefore electrons are not considered explicitly. This assumption is based on the Born-Oppenheimer approximation of the Schrödinger equation (H Ψ = E Ψ), where E is energy of the system, Ψ is the wavefunction and H is the Hamiltonian operator which includes terms for both potential and kinetic energy.
According to the Born-Oppenheimer approximation, nuclei are heavier and move slower than electrons; so movement of electrons can be considered independently of the movement of the nuclei. This makes it possible to analyze factors such as nuclear motions, vibration and rotations separately from electrons which are assumed to move fast enough to adjust to any movement of the nuclei.
Molecular modelling treats a molecule as a "collection of weights connected with springs, where the weights represent the nuclei and the springs represent the bonds."
A Force potential equation is obtained by adding up the energies of every component of the equation. These are energy of every bond (ESTRETCH ), angle (EBEND ), van der waal interactions, dipole diopole interactions, torsions and Emiscellaneous for additional terms.
ETOTAL = ESTRETCH + EBEND + EvdW + EDP-DP + ETORSION + Emiscellaneous
It gives the potential surface energy of a molecule, which determines how a particular atom would move due to movements and displacements of all the other atoms in the system of a molecule.
A quadric form of the Hooke's law formula (harmonic potential), is used to obtain bond stretching/bending energies. This is because the Morse potential form isn't suitable as it is accountable for a wide range of behaviour from the strong equilibrium behaviour to dissociation. It is unlikely for bonds to deviate much from their equilibrium so the Hooke's law is used instead.
The following calculations are examples of some force potentials and their parameters such as those discussed above. They calculate ground state "steric" energies of organic molecules.
Bond stretching:
Ks = force constant in mdyn/Ǻ
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