Molecular recognition explained

The term molecular recognition refers to the specific interaction between two or more molecules through noncovalent bonding such as hydrogen bonding, metal coordination, hydrophobic forces,[1] [2] van der Waals forces, π-π interactions, halogen bonding, or resonant interaction[3] effects. In addition to these direct interactions, solvents can play a dominant indirect role in driving molecular recognition in solution.[4] [5] The host and guest involved in molecular recognition exhibit molecular complementarity. Exceptions are molecular containers,[6] [7] including, e.g., nanotubes, in which portals essentially control selectivity.[8] [9] [10] [11] Selective partioning of molecules between two or more phases can also result in molecular recognition.[12] In partitioning-based molecular recognition the kinetics and equilibrium conditions are governed by the presence of solutes in the two phases.[13]

Biological systems

Molecular recognition plays an important role in biological systems and is observed in between receptor-ligand,[14] [15] antigen-antibody, DNA-protein, sugar-lectin, RNA-ribosome, etc. An important example of molecular recognition is the antibiotic vancomycin that selectively binds with the peptides with terminal D-alanyl-D-alanine in bacterial cells through five hydrogen bonds. The vancomycin is lethal to the bacteria since once it has bound to these particular peptides they are unable to be used to construct the bacteria's cell wall.

Synthetic molecular recognition

Recent work suggests that molecular recognition elements can be synthetically produced at the nano-scale,[16] circumventing the need for naturally occurring molecular recognition elements for the development of sensing tools for small molecules. Bio-mimetic polymers such as molecular imprinted polymers[17] and peptoids can be used to recognize larger biological targets such as proteins [18] and the conjugation of polymers to synthetic fluorescent nanomaterials can generate synthetic macromolecular structures that serve as synthetic antibodies for optical protein recognition and detection.[19] [20]

Supramolecular systems

Chemists have demonstrated that many artificial supramolecular systems can be designed that exhibit molecular recognition.[21] One of the earliest examples of such a system are crown ethers which are capable of selectively binding specific cations. However, a number of artificial systems have since been established.

Static vs. dynamic

Molecular recognition can be subdivided into static molecular recognition and dynamic molecular recognition. Static molecular recognition is likened to the interaction between a key and a keyhole; it is a 1:1 type complexation reaction between a host molecule and a guest molecule to form a host–guest complex. To achieve advanced static molecular recognition, it is necessary to make recognition sites that are specific for guest molecules.

In the case of dynamic molecular recognition the binding of the first guest to the first binding site of a host affects the association constant of a second guest with a second binding site. leading to cooperativity of binding.[22] In the case of positive allosteric systems the binding of the first guest increases the association constant of the second guest. While for negative allosteric systems the binding of the first guest decreases the association constant with the second. The dynamic nature of this type of molecular recognition is particularly important since it provides a mechanism to regulate binding in biological systems.Dynamic molecular recognition may enhance the ability to discriminate between several competing targets via the conformational proofreading mechanism. Dynamic molecular recognition is also being studied for application in highly functional chemical sensors and molecular devices[23]

Complexity

A recent study based on molecular simulations and compliance constants describes molecular recognition as a phenomenon of organisation. Even for small molecules like carbohydrates, the recognition process can not be predicted or designed even assuming that each individual hydrogen bond's strength is exactly known.[24] However, as Mobley et al.[25] concluded, the accurate prediction of the molecular recognition events needs to go beyond the static snapshot of a single frame between the guest and the host. Entropies are key contributors to binding thermodynamics and need to be accounted for in order to predict more accurately the recognition process.[26] Entropies are rarely observable in single bound structures (static snapshot). In proteins, highly-specific recognition can be achieved by evolutionary fine-tuning of chemical interactions, conformational changes, and entropy contributions.[27]

Intragenic complementation

Jehle[28] pointed out that, when immersed in a liquid and intermingled with other molecules, charge fluctuation forces favor the association of identical molecules as nearest neighbors. In accord with this principle, the multiple copies of a polypeptide encoded by a gene often undergo molecular recognition with each other to form an ordered multi-polypeptide protein structure. When such a protein is formed from polypeptides produced by two different mutant alleles of a particular gene, the protein composed of a mixture of polypeptides may exhibit greater functional activity than the multi-polypeptide protein formed by each of the mutants alone. In such a case, the phenomenon is referred to as intragenic complementation.

Intragenic complementation (also called inter-allelic complementation) has been demonstrated in many different genes in a variety of organisms.[29] Crick and Orgel[30] analyzed of the results of such studies and came to the conclusion that intragenic complementation, in general, arises from the interaction of differently defective polypeptide monomers when they form an ordered aggregate they called a “multimer.”

See also

External links

Notes and References

  1. Lockett MR, Lange H, Breiten B, Heroux A, Sherman W, Rappoport D, Yau PO, Snyder PW, Whitesides GM . 6 . The binding of benzoarylsulfonamide ligands to human carbonic anhydrase is insensitive to formal fluorination of the ligand . Angewandte Chemie . 52 . 30 . 7714–7717 . July 2013 . 23788494 . 10.1002/anie.201301813 . 1543705 .
  2. Breiten B, Lockett MR, Sherman W, Fujita S, Al-Sayah M, Lange H, Bowers CM, Heroux A, Krilov G, Whitesides GM . 6 . Water networks contribute to enthalpy/entropy compensation in protein-ligand binding . Journal of the American Chemical Society . 135 . 41 . 15579–15584 . October 2013 . 24044696 . 10.1021/ja4075776 . 17554787 . 10.1.1.646.8648 .
  3. Cosic I . Macromolecular bioactivity: is it resonant interaction between macromolecules?--Theory and applications . IEEE Transactions on Bio-Medical Engineering . 41 . 12 . 1101–1114 . December 1994 . 7851912 . 10.1109/10.335859 . 23892544 .
  4. Baron R, Setny P, McCammon JA . Water in cavity-ligand recognition . Journal of the American Chemical Society . 132 . 34 . 12091–12097 . September 2010 . 20695475 . 2933114 . 10.1021/ja1050082 .
  5. Baron R, McCammon JA . Molecular recognition and ligand association . Annual Review of Physical Chemistry . 64 . 151–175 . 2013 . 23473376 . 10.1146/annurev-physchem-040412-110047 . 2013ARPC...64..151B .
  6. Book: Cram DJ, Cram JM . Container molecules and their guests . Royal Society of Chemistry . Cambridge . 1997 . 978-0-85186-972-8 .
  7. Brotin T, Dutasta JP . Cryptophanes and their complexes--present and future . Chemical Reviews . 109 . 1 . 88–130 . January 2009 . 19086781 . 10.1021/cr0680437 .
  8. Book: Lehn JM . Jean-Marie Lehn . 1995 . Supramolecular Chemistry . . . 978-3-527-29312-4 . 315928178.
  9. Gellman SH . Introduction: Molecular Recognition . Chemical Reviews . 97 . 5 . 1231–1232 . August 1997 . 11851448 . 10.1021/cr970328j .
  10. Book: Chatterji D . Basics of Molecular Recognition . 2016 . CRC Press . Boca Raton, FL . 978-1-4822-1968-5.
  11. Book: Rotello V, Thayumanavan S . Molecular recognition and polymers : control of polymer structure and self-assembly . 2008 . Wiley . Hoboken, N.J. . 978-0-470-27738-6.
  12. Bell TN, Feng K, Calvin G, Van Winkle DH, Lenhert S . Organic Composomes as Supramolecular Aptamers . ACS Omega . 5 . 42 . 27393–27400 . October 2020 . 33134702 . 10.1021/acsomega.0c03799 . free . 7594120 .
  13. Zhou H, Shiel E, Bell T, Lin S, Lenhert S . Kinetic Mechanism of Surfactant-Based Molecular Recognition: Selective Permeability across an Oil–Water Interface Regulated by Supramolecular Aggregates . The Journal of Physical Chemistry B . 127 . 47 . 10201–10214 . November 2023 . 37972386 . 10.1021/acs.jpcb.3c05017 .
  14. Lockett MR, Lange H, Breiten B, Heroux A, Sherman W, Rappoport D, Yau PO, Snyder PW, Whitesides GM . 6 . The binding of benzoarylsulfonamide ligands to human carbonic anhydrase is insensitive to formal fluorination of the ligand . Angewandte Chemie . 52 . 30 . 7714–7717 . July 2013 . 23788494 . 10.1002/anie.201301813 . 1543705 .
  15. Breiten B, Lockett MR, Sherman W, Fujita S, Al-Sayah M, Lange H, Bowers CM, Heroux A, Krilov G, Whitesides GM . 6 . Water networks contribute to enthalpy/entropy compensation in protein-ligand binding . Journal of the American Chemical Society . 135 . 41 . 15579–15584 . October 2013 . 24044696 . 10.1021/ja4075776 . 17554787 . 10.1.1.646.8648 .
  16. Zhang J, Landry MP, Barone PW, Kim JH, Lin S, Ulissi ZW, Lin D, Mu B, Boghossian AA, Hilmer AJ, Rwei A, Hinckley AC, Kruss S, Shandell MA, Nair N, Blake S, Şen F, Şen S, Croy RG, Li D, Yum K, Ahn JH, Jin H, Heller DA, Essigmann JM, Blankschtein D, Strano MS . 6 . Molecular recognition using corona phase complexes made of synthetic polymers adsorbed on carbon nanotubes . Nature Nanotechnology . 8 . 12 . 959–968 . December 2013 . 24270641 . 5051352 . 10.1038/nnano.2013.236 . 2013NatNa...8..959Z .
  17. Sullivan MV, Dennison SR, Archontis G, Reddy SM, Hayes JM . Toward Rational Design of Selective Molecularly Imprinted Polymers (MIPs) for Proteins: Computational and Experimental Studies of Acrylamide Based Polymers for Myoglobin . The Journal of Physical Chemistry B . 123 . 26 . 5432–5443 . July 2019 . 31150581 . 10.1021/acs.jpcb.9b03091 . 172137800 .
  18. Mannige RV, Haxton TK, Proulx C, Robertson EJ, Battigelli A, Butterfoss GL, Zuckermann RN, Whitelam S . 6 . Peptoid nanosheets exhibit a new secondary-structure motif . Nature . 526 . 7573 . 415–420 . October 2015 . 26444241 . 10.1038/nature15363 . 205245623 . 2015Natur.526..415M .
  19. Sullivan MV, Stockburn WJ, Hawes PC, Mercer T, Reddy SM . Green synthesis as a simple and rapid route to protein modified magnetic nanoparticles for use in the development of a fluorometric molecularly imprinted polymer-based assay for detection of myoglobin . Nanotechnology . 32 . 9 . 095502 . February 2021 . 33242844 . 8314874 . 10.1088/1361-6528/abce2d . 2021Nanot..32i5502S .
  20. Book: 8. 3. 197–223. Beyene AG, Demirer GS, Landry MP . Nanoparticle-Templated Molecular Recognition Platforms for Detection of Biological Analytes. Current Protocols in Chemical Biology. 2009-01-01. John Wiley & Sons, Inc.. 9780470559277. en. 10.1002/cpch.10. 27622569. 10539024. 5249925.
  21. Biedermann F, Schneider HJ . Experimental Binding Energies in Supramolecular Complexes . Chemical Reviews . 116 . 9 . 5216–5300 . May 2016 . 27136957 . 10.1021/acs.chemrev.5b00583 .
  22. Shinkai S, Ikeda M, Sugasaki A, Takeuchi M . Positive allosteric systems designed on dynamic supramolecular scaffolds: toward switching and amplification of guest affinity and selectivity . Accounts of Chemical Research . 34 . 6 . 494–503 . June 2001 . 11412086 . 10.1021/ar000177y .
  23. McBride JM, Eckmann JP, Tlusty T . General Theory of Specific Binding: Insights from a Genetic-Mechano-Chemical Protein Model . Molecular Biology and Evolution . 39 . 11 . November 2022 . 36208205 . 9641994 . 10.1093/molbev/msac217 .
  24. Grunenberg J . Complexity in molecular recognition . Physical Chemistry Chemical Physics . 13 . 21 . 10136–10146 . June 2011 . 21503359 . 10.1039/C1CP20097F . 2011PCCP...1310136G .
  25. Mobley DL, Dill KA . Binding of small-molecule ligands to proteins: "what you see" is not always "what you get" . Structure . 17 . 4 . 489–498 . April 2009 . 19368882 . 2756098 . 10.1016/j.str.2009.02.010 .
  26. Schmidtchen FP . Hosting anions. The energetic perspective . Chemical Society Reviews . 39 . 10 . 3916–3935 . October 2010 . 20820595 . 10.1039/C0CS00038H .
  27. McBride JM, Eckmann JP, Tlusty T . General Theory of Specific Binding: Insights from a Genetic-Mechano-Chemical Protein Model . Molecular Biology and Evolution . 39 . 11 . msac217 . November 2022 . 36208205 . 9641994 . 10.1093/molbev/msac217 . Echave J .
  28. Jehle H . Intermolecular forces and biological specificity. . Proceedings of the National Academy of Sciences of the United States of America . 50 . 3 . 516–24 . September 1963 . 16578546 . 221211 . 10.1073/pnas.50.3.516 . 1963PNAS...50..516J . free .
  29. Bernstein H, Edgar RS, Denhardt GH . Intragenic complementation among temperature sensitive mutants of bacteriophage T4D . Genetics . 51 . 6 . 987–1002 . June 1965 . 14337770 . 1210828 . 10.1093/genetics/51.6.987 .
  30. Crick FH, Orgel LE . The theory of inter-allelic complementation . Journal of Molecular Biology . 8 . 161–5 . January 1964 . 14149958 . 10.1016/s0022-2836(64)80156-x .

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