molecular binding

Molecular binding can be classified into the following types:{{cite journal | vauthors = Smith AJ, Zhang X, Leach AG, Houk KN | title = Beyond picomolar affinities: quantitative aspects of noncovalent and covalent binding of drugs to proteins | journal = Journal of Medicinal Chemistry | volume = 52 | issue = 2 | pages = 225–33 | date = Jan 2009 | pmid = 19053779 | pmc = 2646787 | doi = 10.1021/jm800498e }}

• Non-covalent – no chemical bonds are formed between the two interacting molecules hence the association is fully reversible
• Reversible covalent – 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 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 associations.{{cite journal | url = http://goldbook.iupac.org/C01203.html | title = Definition of a molecular complex | date = 2012-08-19 | journal = Compendium of Chemical Terminology: Gold Book | publisher = International Union of Pure and Applied Chemistry | doi = 10.1351/goldbook.C01203 | quote = "A molecular entity formed by loose association involving two or more component molecular entities (ionic or uncharged), or the corresponding chemical species. The bonding between the components is normally weaker than in a covalent bond. The term has also been used with a variety of shades of meaning in different contexts: it is therefore best avoided when a more explicit alternative is applicable. In inorganic chemistry the term 'coordination entity' is recommended instead of 'complex'." | doi-access = free }} Non-covalent interactions can effectively become irreversible; for example, tight binding inhibitors of enzymes can have kinetics that closely resemble irreversible covalent inhibitors. Among the tightest known protein–protein complexes is that between the enzyme angiogenin and ribonuclease inhibitor; the dissociation constant for the human proteins is 5x10⁻¹⁶ mol/L.{{cite journal | vauthors = Papageorgiou AC, Shapiro R, Acharya KR | title = Molecular recognition of human angiogenin by placental ribonuclease inhibitor--an X-ray crystallographic study at 2.0 A resolution | journal = The EMBO Journal | volume = 16 | issue = 17 | pages = 5162–77 | date = Sep 1997 | pmid = 9311977 | doi = 10.1093/emboj/16.17.5162 | pmc=1170149}}{{cite journal | vauthors = Dickson KA, Haigis MC, Raines RT | title = Ribonuclease inhibitor: structure and function | journal = Progress in Nucleic Acid Research and Molecular Biology | volume = 80 | pages = 349–374 | date = 2005 | pmid = 16164979 | pmc = 2811166 | doi = 10.1016/S0079-6603(05)80009-1 | isbn = 9780125400800 }} Another biological example is the binding protein streptavidin, which has extraordinarily high affinity for biotin (vitamin B7/H, dissociation constant, K_d ≈10⁻¹⁴ mol/L).{{cite journal | vauthors = Green NM | title = Avidin | journal = Advances in Protein Chemistry | volume = 29 | pages = 85–133 | year = 1975 | pmid = 237414 | doi = 10.1016/s0065-3233(08)60411-8 | isbn = 9780120342297 }} 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.{{cite journal | vauthors = Holmberg A, Blomstergren A, Nord O, Lukacs M, Lundeberg J, Uhlén M | title = The biotin-streptavidin interaction can be reversibly broken using water at elevated temperatures | journal = Electrophoresis | volume = 26 | issue = 3 | pages = 501–510 | date = Feb 2005 | pmid = 15690449 | doi = 10.1002/elps.200410070 | s2cid = 16058388 }} An example of change in local concentration causing dissociation can be found in the Bohr effect, which describes the dissociation of ligands from hemoglobin in the lung versus peripheral tissues.

Some protein–protein interactions result in covalent bonding,{{cite journal | vauthors = Westermarck J, Ivaska J, Corthals GL | title = Identification of protein interactions involved in cellular signaling | journal = Molecular & Cellular Proteomics | volume = 12 | issue = 7 | pages = 1752–63 | date = Jul 2013 | pmid = 23481661 | pmc = 3708163 | doi = 10.1074/mcp.R113.027771 | doi-access = free }} and some pharmaceuticals are irreversible antagonists that may or may not be covalently bound.{{cite book | last1 = Rang | first1 = Humphrey P. | last2 = Ritter | first2 = James M. | title = Rang and Dale's pharmacology | date = 2007 | publisher = Churchill Livingstone/Elsevier | location = Philadelphia, PA | isbn = 978-0-443-06911-6 | page = 19 | edition = 6th | name-list-style = vanc }} Drug discovery has been through periods when drug candidates that bind covalently to their targets are attractive and then are avoided; the success of bortezomib made boron-based covalently binding candidates more attractive in the late 2000s.{{cite journal | vauthors = Hunter P | title = Not boring at all. Boron is the new carbon in the quest for novel drug candidates | journal = EMBO Reports | volume = 10 | issue = 2 | date = Feb 2009 | pmid = 19182828 | doi = 10.1038/embor.2009.2 | pages=125–8 | pmc=2637326}}{{cite journal | vauthors = London N, Miller RM, Krishnan S, Uchida K, Irwin JJ, Eidam O, Gibold L, Cimermančič P, Bonnet R, Shoichet BK, Taunton J | title = Covalent docking of large libraries for the discovery of chemical probes | journal = Nature Chemical Biology | volume = 10 | issue = 12 | date = Dec 2014 | pmid = 25344815 | doi = 10.1038/nchembio.1666 | pages=1066–72 | pmc=4232467}}

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-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. Alternatively, the binding may be enthalpy-driven where non-covalent attractive forces such as electrostatic attraction, hydrogen bonding, and van der Waals / London dispersion forces are primarily responsible for the formation of a stable complex.{{cite journal | vauthors = Miyamoto S, Kollman PA | title = What determines the strength of noncovalent association of ligands to proteins in aqueous solution? | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 18 | pages = 8402–6 | date = Sep 1993 | pmid = 8378312 | pmc = 47364 | doi = 10.1073/pnas.90.18.8402 | bibcode = 1993PNAS...90.8402M | doi-access = free }} 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.{{cite journal | vauthors = Cooper A | title = Thermodynamic analysis of biomolecular interactions | journal = Current Opinion in Chemical Biology | volume = 3 | issue = 5 | pages = 557–63 | date = Oct 1999 | pmid = 10508661 | doi = 10.1016/S1367-5931(99)00008-3 }}

The strength of binding between the components of molecular complex is measured quantitatively by the binding constant (K_A), 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:

:$A+B\; \backslash rightleftharpoons\; AB:\backslash log\; K\_\{A\}\; =\backslash log\; \backslash left(\backslash frac\{[AB]\}\{[A][B]\}\; \backslash right)=-pK\_\{A\}$

When the molecular complex prevents the normal functioning of an enzyme, the binding constant is also referred to as inhibition constant (K_I).

Molecules that can participate in molecular binding include proteins, nucleic acids, carbohydrates, lipids, and small organic molecules such as drugs. Hence the types of complexes that form as a result of molecular binding include:

• protein–protein{{cite book | first1 = Haian | last1 = Fu | title = Protein–protein interactions: methods and applications | publisher = Humana Press | location = Totowa, NJ | year = 2004 | isbn = 1-58829-120-0 | name-list-style = vanc }}
• protein–DNA{{cite book | first1 = Harald | last1 = Seitz | title = Analytics of Protein–DNA Interactions (Advances in Biochemical Engineering / Biotechnology) | publisher = Springer | location = Berlin | year = 2007 | isbn = 978-3-540-48147-8 | name-list-style = vanc }}
• protein–hormone
• protein–drug{{cite book | first1 = Gerd | last1 = Folkers | first2 = Hans-Joachim | last2 = Böhm | first3 = Gisbert | last3 = Schneider | first4 = Raimund | last4 = Mannhold | first5 = Hugo | last5 = Kubinyi | title = Protein–ligand interactions from molecular recognition to drug design | publisher = Wiley-VCH | location = Weinheim | year = 2003 | isbn = 3-527-30521-1 | name-list-style = vanc }}

Proteins that form stable complexes with other molecules are often referred to as receptors while their binding partners are called ligands.{{cite book | last1 = Klotz | first1 = Irving M. | title = Ligand-receptor energetics: a guide for the perplexed | publisher = John Wiley & Sons | location = Chichester | year = 1997 | isbn = 0-471-17626-5 | name-list-style = vanc }}

• Receptor (biochemistry)
• Supramolecular chemistry

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{{Pharmacology}}

Category:Medicinal chemistry

Category:Molecular physics