But first, let's get a better defintion of what a ligand is...
1. The biological function of a protein typically depends on the structure of specific binding sites. These sites are located at the surface of the protein and are determined by geometrical arrangements and physico-chemical properties of tens of non-hydrogen atoms.
The ability of proteins to form specific stable complexes is fundamental to biological existence. The interaction between ligand and protein takes place at the surface of the protein. This surface is very complex and convoluted. Furthermore, bound ligands vary greatly in size and properties. The smallest ligands such as O2 and NO consist of two covalently linked atoms showing no or only partial atomic charges. Interactions between proteins and ligands of this type are defined by special arrangement of the electron systems of each participant. Likewise, small ions, e.g. calcium, sodium etc., form a complex compound or similar structure with a few special charged atoms of the protein. A large number of known protein ligands are prosthetic groups, substrates and coenzymes. Their molecular masses lie between 100 and about 2000 Da and their binding sites are larger and more complex. The other end of the size scale is defined by the largest interacting partners of proteins: other biological polymers like nucleic acids, other proteins, and polysaccharides. They show molecular masses from 5000 up to 100,000 Da and more.
[The] binding sites of smaller ligands seem to be little caves (grooves, pockets, cavities, depressions) at the surface of proteins. (ref.)
2. A ligand refers to a speciﬁc molecule that can bind to a protein. With respect to viruses, a ligand is a protein on the outer coat of a virus that can bind to a receptor protein on the surface of a cell that the virus will infect. Ligands on the surface of a virus can only bind with speciﬁc receptor proteins. Different cell types contain different receptor proteins.(ref.)
3. A ligand is simply a molecule which interacts with a protein, by specifically binding to the protein. You should not make the mistake of thinking of a ligand as a relatively small molecule, involved in some obscure biochemical pathway. This narrow view is incorrect. For example consider the case of a repressor protein involved in the regulation of a gene. The repressor protein binds specifically to a section of chromosomal DNA in order to prevent that gene being expressed. In this case, DNA is the ligand (see opposite). This example also illustrates another important aspect of protein ligand binding which is that the interaction must be specific. The interior of the cell contains many different potential ligands and the protein must interact only with the appropriate molecule. So a ligand can be a nucleic acid, polysaccharide, lipid or even another protein. Protein ligand binding is involved in many cell functions including hormone receptors, gene regulation, transport across membranes, the immune response and enzymes catalysis. Although you may not think of an enzyme catalysed reaction as protein ligand binding, initially the enzyme (protein) must bind to the substrate (ligand) before any chemical changes occur.
An example shown in the diagram at left is a gene regulating protein which binds specifically to DNA preventing transcription. The two chains of DNA on the left of the picture are shaded differently. There are two polypeptide chains shown on the right of the picture. In this case we can see that the protein which binds the DNA ligand is a dimer i.e. composed of two separate polypeptide chains.
Any binding of a ligand to a protein is also reversible. The physical interactions between a protein and ligand are the same as those between the protein and water molecules or hydrogen ions for example but these latter molecules do not bind to the protein at a specific site. The ligand will however bind to the protein at a specific site. This site has the necessary physical characteristics to make ligand binding favourable.
The specificity of a binding site for a particular ligand can vary however depending on the structure of the protein. For example, the protein may be able to bind two different ligands and each of these ligands will then compete for the proteins binding site. Typically, these different ligand molecules will share some structural or physical properties and thus both be able to fit into the binding site on the protein. This is known as competitive binding.
In some cases, there may be more than one binding site on the protein molecule. Two different ligand or two similar ligands may be able to bind to the protein, one at each binding site. This allosteric binding is quite common in biological systems. Haemoglobin binding to oxygen is perhaps the most commonly cited example of this. You may already be familiar with allosteric regulation of enzyme action.
Summary of Protein Ligand Binding
4. Electrostatic steering and ionic tethering in enzyme-ligand binding.
Although the driving force for ligand binding is often ascribed to the hydrophobic effect, electrostatic interactions also influence the binding process of both charged and nonpolar ligands. Electrostatic steering of charged substrates into enzyme active sites [conserves] electrostatic potential [energy] localized at the active sites and are the primary determinants of the bimolecular association rates. A more subtle effect is "ionic tethering: salt links can act as tethers between structural elements of an enzyme that undergo conformational change upon substrate binding, and thereby regulate or modulate substrate binding. Ionic tethering can provide a control mechanism for substrate binding that is sensitive to the electrostatic properties of the enzyme's surroundings even when the substrate is nonpolar