A ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand’s electron pairs.
Ligands are usually thought of as electron donors attracted to the metal at the center of the complex. Metals are electron acceptors. Ligands may be neutral or negatively charged species with electron pairs available.
Ligands are signaling molecules that cause modulation of processes inside cells by binding to receptors. Intracellular ligands, such as nitric oxide and estrogen, are small and hydrophobic and diffuse directly through the cell membrane to activate proteins. The receptors then mediate changes internally.
The ligand travels through the watery fluids of an organism, within the blood, tissues, or within a cell itself. The ligand travels at random, but once the concentration is high enough, a ligand will eventually reach a protein. Proteins receiving ligands can be receptors, channels, and can even be the start of a complex series of intertwined proteins. When the ligand binds to the protein, it undergoes a conformational change. This means that while no chemical bonds have been formed or broken, the physical action of the ligand fitting into the protein changes the overall shape of the entire structure. This can trigger many actions. In most cases, the movement of the protein itself activates another chemical pathway, or triggers the release of another messenger ligand, to carry the message to other receptors.
The reversibility of the bond between ligand and protein is a crucial aspect of all forms of life. If ligands bound irreversibly, they could not serve as messengers, and most biological processes would fall apart. If ligands were changed, the way an enzyme changes changes a substrate, the ligand would become something else after the interaction, and could not be as easily recycled as a messenger. Biologically active proteins are active because of their shape. This shape interacts with the chemistry of the ligand to create a stable connection between the two molecules, which will eventually reverse, leaving both molecules the same. In a substrate and enzyme reaction, the substrate is permanently changed.
The affinity of a particular ligand for a particular protein is determined entirely by its chemical makeup and that of the binding site of the protein. At the binding site, amino acids will be exposed which tend to complement the desired ligand. The amino acids will match the ligand in certain aspects.
The term “monodentate” can be translated as “one tooth,” referring to the ligand binding to the center through only one atom. Some examples of monodentate ligands are: chloride ions, water, hydroxide, and ammonia.
Bidentate ligands have two donor atoms which allow them to bind to a central metal atom or ion at two points. Common examples of bidentate ligands are ethylenediamine and the oxalate ion.
Polydentate ligands range in the number of atoms used to bond to a central metal atom or ion. EDTA, a hexadentate ligand, is an example of a polydentate ligand that has six donor atoms with electron pairs that can be used to bond to a central metal atom or ion.
Ambidentate ligands are monodentate ligands that can bind in two possible places. For example, the nitrate ion NO2– can bind to the central metal atom/ion at either the nitrogen atom or one of the oxygen atoms. The thiocyanate ion, SCN– can bind to the central metal at either the sulfur or the nitrogen.
Ligands of proteins can be characterized also by the number of protein chains they bind. “Monodesmic” ligands are ligands that bind a single protein chain, while “polydesmic” ligands are frequent in protein complexes, and are ligands that bind more than one protein chain, typically in or near protein interfaces. Recent research shows that the type of ligands and binding site structure has profound consequences for the evolution, function, allostery and folding of protein complexes.
Selective ligands have a tendency to bind to very limited kinds of receptors, whereas non-selective ligands bind to several types of receptors. This plays an important role in pharmacology, where drugs that are non-selective tend to have more adverse effects, because they bind to several other receptors in addition to the one generating the desired effect.
For hydrophobic ligands (e.g. PIP2) in complexes with a hydrophobic protein (e.g. lipid-gated ion channels) determining the affinity is complicated by non-specific hydrophobic interactions.
Main methods to study protein–ligand interactions are;
- Fourier transform spectroscopy
- Raman spectroscopy
- Fluorescence spectroscopy
- Circular dichroism
- Nuclear magnetic resonance
- Mass spectrometry
- Atomic force microscope
- Paramagnetic probes
- Dual polarization interferometry
- Multi-parametric surface plasmon resonance
- Ligand binding assay and radioligand binding assay