Molecular binding is an attractive interaction between two
molecule
A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioch ...
s that results in a stable association in which the molecules are in close proximity to each other. It is formed when atoms or molecules bind together by sharing of electrons. It often, but not always, involves some
chemical bond
A chemical bond is a lasting attraction between atoms or ions that enables the formation of molecules and crystals. The bond may result from the electrostatic force between oppositely charged ions as in ionic bonds, or through the sharing of ...
ing.
In some cases, the associations can be quite strong—for example, the protein
streptavidin
Streptavidin is a 66.0 (tetramer) kDa protein purified from the bacterium '' Streptomyces avidinii''. Streptavidin homo-tetramers have an extraordinarily high affinity for biotin (also known as vitamin B7 or vitamin H). With a dissociation co ...
and the vitamin
biotin
Biotin (or vitamin B7) is one of the B vitamins. It is involved in a wide range of metabolic processes, both in humans and in other organisms, primarily related to the utilization of fats, carbohydrates, and amino acids. The name ''biotin'', bor ...
have a
dissociation constant
In chemistry, biochemistry, and pharmacology, a dissociation constant (K_D) is a specific type of equilibrium constant that measures the propensity of a larger object to separate (dissociate) reversibly into smaller components, as when a complex fa ...
(reflecting the ratio between bound and free biotin) on the order of 10
−14—and so the reactions are effectively irreversible. The result of molecular binding is sometimes the formation of a molecular complex in which the attractive forces holding the components together are generally
non-covalent
In chemistry, a non-covalent interaction differs from a covalent bond in that it does not involve the sharing of electrons, but rather involves more dispersed variations of electromagnetic interactions between molecules or within a molecule. The c ...
, and thus are normally energetically weaker than
covalent bond
A covalent bond is a chemical bond that involves the sharing of electrons to form electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs. The stable balance of attractive and repulsive forces between atoms ...
s.
Molecular binding occurs in biological complexes (e.g., between pairs or sets of proteins, or between a protein and a small molecule
ligand
In coordination chemistry, 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 electr ...
it binds) and also in abiologic chemical systems, e.g. as in cases of ''
coordination polymers
A coordination polymer is an inorganic or organometallic polymer structure containing metal cation centers linked by ligands. More formally a coordination polymer is a coordination compound with repeating coordination entities extending in 1, 2, o ...
'' and ''coordination networks'' such as
metal-organic frameworks.
Types
Molecular binding can be classified into the following types:
*
non-covalent
In chemistry, a non-covalent interaction differs from a covalent bond in that it does not involve the sharing of electrons, but rather involves more dispersed variations of electromagnetic interactions between molecules or within a molecule. The c ...
– no chemical bonds are formed between the two interacting molecules hence the association is fully reversible
* reversible
covalent
A covalent bond is a chemical bond that involves the sharing of electrons to form electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs. The stable balance of attractive and repulsive forces between atoms ...
– a chemical bond is formed, however the
free energy difference separating the noncovalently-bonded reactants from bonded product is near
equilibrium and the
activation barrier
In chemistry and physics, activation energy is the minimum amount of energy that must be provided for compounds to result in a chemical reaction. The activation energy (''E''a) of a reaction is measured in joules per mole (J/mol), kilojoules p ...
is relatively low such that the reverse reaction which cleaves the chemical bond easily occurs
* irreversible covalent – a chemical bond is formed in which the product is
thermodynamically much more stable than the reactants such that the reverse reaction does not take place.
Bound molecules are sometimes called a "molecular complex"—the term generally refers to
non-covalent
In chemistry, a non-covalent interaction differs from a covalent bond in that it does not involve the sharing of electrons, but rather involves more dispersed variations of electromagnetic interactions between molecules or within a molecule. The c ...
associations.
Non-covalent interactions can effectively become irreversible; for example,
tight binding inhibitors of
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
s can have kinetics that closely resemble irreversible covalent inhibitors. Among the tightest known protein–protein complexes is that between the enzyme
angiogenin
Angiogenin (ANG) also known as ribonuclease 5 is a small 123 amino acid protein that in humans is encoded by the ''ANG'' gene. Angiogenin is a potent stimulator of new blood vessels through the process of angiogenesis. Ang hydrolyzes cellular R ...
and
ribonuclease inhibitor
Ribonuclease inhibitor (RI) is a large (~450 residues, ~49 kDa), acidic (pI ~4.7), leucine-rich repeat protein that forms extremely tight complexes with certain ribonucleases. It is a major cellular protein, comprising ~0.1% of all cellular prot ...
; the dissociation constant for the human proteins is 5x10
−16 mol/L. Another biological example is the binding protein
streptavidin
Streptavidin is a 66.0 (tetramer) kDa protein purified from the bacterium '' Streptomyces avidinii''. Streptavidin homo-tetramers have an extraordinarily high affinity for biotin (also known as vitamin B7 or vitamin H). With a dissociation co ...
, which has extraordinarily high affinity for
biotin
Biotin (or vitamin B7) is one of the B vitamins. It is involved in a wide range of metabolic processes, both in humans and in other organisms, primarily related to the utilization of fats, carbohydrates, and amino acids. The name ''biotin'', bor ...
(vitamin B7/H,
dissociation constant
In chemistry, biochemistry, and pharmacology, a dissociation constant (K_D) is a specific type of equilibrium constant that measures the propensity of a larger object to separate (dissociate) reversibly into smaller components, as when a complex fa ...
, K
d ≈10
−14 mol/L).
In such cases, if the reaction conditions change (e.g., the protein moves into an environment where biotin concentrations are very low, or pH or ionic conditions are altered), the reverse reaction can be promoted. For example, the biotin-streptavidin interaction can be broken by incubating the complex in water at 70 °C, without damaging either molecule. An example of change in local concentration causing dissociation can be found in the
Bohr effect
The Bohr effect is a phenomenon first described in 1904 by the Danish physiologist Christian Bohr. Hemoglobin's oxygen binding affinity (see oxygen–haemoglobin dissociation curve) is inversely related both to acidity and to the concentration o ...
, which describes the dissociation of ligands from
hemoglobin
Hemoglobin (haemoglobin BrE) (from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globus'' 'ball, sphere' + ''-in'') (), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein present in red blood cells (erythrocyte ...
in the lung versus peripheral tissues.
[
Some protein–protein interactions result in ]covalent bonding
A covalent bond is a chemical bond that involves the sharing of electrons to form electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs. The stable balance of attractive and repulsive forces between atoms ...
, and some pharmaceuticals
A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and rel ...
are irreversible antagonist
An irreversible antagonist is a type of antagonist that binds permanently to a receptor, either by forming a covalent bond to the active site, or alternatively just by binding so tightly that the rate of dissociation is effectively zero at rele ...
s that may or may not be covalently bound. Drug discovery
In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which new candidate medications are discovered.
Historically, drugs were discovered by identifying the active ingredient from traditional remedies or by ...
has been through periods when drug candidates that bind covalently to their targets are attractive and then are avoided; the success of bortezomib
Bortezomib, sold under the brand name Velcade among others, is an anti-cancer medication used to treat multiple myeloma and mantle cell lymphoma. This includes multiple myeloma in those who have and have not previously received treatment. It is ...
made boron
Boron is a chemical element with the symbol B and atomic number 5. In its crystalline form it is a brittle, dark, lustrous metalloid; in its amorphous form it is a brown powder. As the lightest element of the ''boron group'' it has th ...
-based covalently binding candidates more attractive in the late 2000s.
Driving force
In order for the complex to be stable, the free energy of complex by definition must be lower than the solvent separated molecules. The binding may be primarily entropy
Entropy is a scientific concept, as well as a measurable physical property, that is most commonly associated with a state of disorder, randomness, or uncertainty. The term and the concept are used in diverse fields, from classical thermodynam ...
-driven (release of ordered solvent molecules around the isolated molecule that results in a net increase of entropy of the system). When the solvent is water, this is known as the hydrophobic effect
The hydrophobic effect is the observed tendency of nonpolar substances to aggregate in an aqueous solution and exclude water molecules. The word hydrophobic literally means "water-fearing", and it describes the segregation of water and nonpolar ...
. Alternatively the binding may be enthalpy
Enthalpy , a property of a thermodynamic system, is the sum of the system's internal energy and the product of its pressure and volume. It is a state function used in many measurements in chemical, biological, and physical systems at a constant ...
-driven where non-covalent attractive forces such as electrostatic
Electrostatics is a branch of physics that studies electric charges at rest (static electricity).
Since classical times, it has been known that some materials, such as amber, attract lightweight particles after rubbing. The Greek word for amber ...
attraction, hydrogen bonding
In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a l ...
, and van der Waals / London dispersion force
London dispersion forces (LDF, also known as dispersion forces, London forces, instantaneous dipole–induced dipole forces, fluctuating induced dipole bonds or loosely as van der Waals forces) are a type of intermolecular force acting between at ...
s are primarily responsible for the formation of a stable complex. Complexes that have a strong entropy contribution to formation tend to have weak enthalpy contributions. Conversely complexes that have strong enthalpy component tend to have a weak entropy component. This phenomenon is known as enthalpy-entropy compensation.
Measurement
The strength of binding between the components of molecular complex is measured quantitatively by the binding constant
The binding constant, or affinity constant/association constant, is a special case of the equilibrium constant ''K'', and is the inverse of the dissociation constant. It is associated with the binding and unbinding reaction of receptor (R) and lig ...
(KA), defined as the ratio of the concentration of the complex divided by the product of the concentrations of the isolated components at equilibrium in molar units.
:
When the molecular complex prevents the normal functioning of an enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
, the binding constant
The binding constant, or affinity constant/association constant, is a special case of the equilibrium constant ''K'', and is the inverse of the dissociation constant. It is associated with the binding and unbinding reaction of receptor (R) and lig ...
is also referred to as inhibition constant
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usually a mole ...
(KI).
Examples
Molecules that can participate in molecular binding include proteins
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
, nucleic acids
Nucleic acids are biopolymers, macromolecules, essential to all known forms of life. They are composed of nucleotides, which are the monomers made of three components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main clas ...
, carbohydrates
In organic chemistry, a carbohydrate () is a biomolecule consisting of carbon (C), hydrogen (H) and oxygen (O) atoms, usually with a hydrogen–oxygen atom ratio of 2:1 (as in water) and thus with the empirical formula (where ''m'' may or may ...
, lipids
Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include ...
, and small organic molecules such as drugs
A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via inhalat ...
. Hence the types of complexes that form as a result of molecular binding include:
* protein–protein
* protein– DNA
* protein–hormone
A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...
* protein–drug
Proteins that form stable complexes with other molecules are often referred to as receptors
Receptor may refer to:
*Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a n ...
while their binding partners are called ligand
In coordination chemistry, 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 electr ...
s.
See also
* Receptor (biochemistry)
In biochemistry and pharmacology, receptors are chemical structures, composed of protein, that receive and transduce signals that may be integrated into biological systems. These signals are typically chemical messengers which bind to a recept ...
* Supramolecular chemistry
Supramolecular chemistry refers to the branch of chemistry concerning chemical systems composed of a discrete number of molecules. The strength of the forces responsible for spatial organization of the system range from weak intermolecular forces, ...
References
{{Pharmacology
Medicinal chemistry
Molecular physics