**2. Non-covalent interactions**

Non-covalent interactions are chemical bonds that do not involve sharing of electron pairs between orbitals of different atoms, there are no orbital overlapping in these interactions which have an electrostatic nature and are not highly directional. Covalent bonds are generally shorter than 2Å while the non-covalent ones are within the range of several angstroms. Another difference between these two types of bonds is the energy released in its formation, non-covalent interactions are weaker, with energies below 40 kJ/mol whereas covalent bonds energies range 80-800 kJ/mol.

These weak interactions have important roles in the binding of macromolecules with each other and with other molecules in the cell, in the mainteinance of the three dimensional structure of large macromolecules such as proteins or nucleic acids (e.g. DNA double helix) and they are the forces found in the majority of the drug-proteins interactions in pharmacology.

## **2.1 Types of non-covalent interactions**

There are four commonly mentioned fundamental non-covalent interaction types including ionic interactions, hydrogen bonds, hydrophobic interactions and van der Waals forces (dispersion attractions, dipole-dipole and dipole-induced dipole interactions). All these weak interactions must work together to have significant effects. Their combined bond effect is greater than the sum of the individual ones. The free energy of multiple bonds between two molecules is different than the sum of the enthalpies of each bond due to entropic effects.

### **2.1.1 Ionic interactions**

Ionic bonds result from the electrostatic attraction between two ionized groups of opposite charge such as carboxyl (-COO-) and amino (-NH3 +). These ionic interactions are directly proportional to the product of the interacting charges and inversely proportional to the dielectric constant of the medium and the distance separating the charges. This relationship is defined by Coulomb's law:

$$\mathbf{E} = \frac{\mathbf{k} \mathbf{q}\_1 \mathbf{q}\_2}{\mathbf{D} \mathbf{r}} \tag{1}$$

where E is the energy, q1 and q2 are the charges of two atoms, r is the distance between them, D is the dielectric constant, and k is a proportionality constant. A charged group on a molecule can attract an oppositely charged group from another molecule. By contract, an attractive interaction has a negative energy. The dielectric constant is important for the medium. In water, these bonds are very weak as the dielectric constant is much higher (D=80) than in vacuum (D=1). As an example, the electrostatic interaction between two atoms bearing single opposite charges separated by 3 Å in water has an energy of 5.9 kJ/mol (k=1389 kJ/mol).
