‘Potentization’- A Phenomenon Belonging To The Domain Of Supra-molecular Chemistry

Study of ‘Molecular Imprinting’ involved in homeopathic ‘potentization’, as well as the ‘biological mechanism’ of therapeutic actions of potentized drugs belong to the domain of SUPRA-MOLECULAR CHEMISTRY, rather than CHEMISTRY or BIOCHEMISTRY. Molecular imprints contained in potentized drugs, and their biological actions may be considered exactly as  APPLIED BIOMIMETIC ARCHITECTURES.

Supramolecular chemistry refers to the study of supra-molecular systems, and focuses on the peculiar molecular formations made up of a discrete number of assembled molecular subunits or components. The forces responsible for the supra-molecular spatial organization are mostly those weak intermolecular forces and electrostatic or hydrogen bonding.  In certain cases, strong covalent bonding are also involved, provided that the degree of electronic coupling between the molecular component remains small with respect to relevant energy parameters of the component.

While traditional chemistry focuses on the covalent bonding involved in formation of stable chemical ‘molecules’,  supra-molecular chemistry studies the weaker and reversible ‘non-covalent’ interactions between molecules. These ‘non-covalent’ forces include hydrogen bonding, metal coordination, hydrophobic forces, van der Waals forces, pi-pi interactions and electrostatic effects.

Supra-molecular chemistry studies the phenomena such as molecular self-assembly, protein folding, molecular recognition, host-guest chemistry, mechanically-interlocked molecular architectures, and dynamic covalent chemistry.

The study of non-covalent interactions and supra-molecular formations is crucial to understanding many biological processes such as cell structure, biomolecular interactions, molecular recognition, protein kinetics, ligand-target interactions, antigen-antibody interactions, genetic expression, molecular inbitions, proteinopathies  etc. Study of biological systems is often the inspiration for supra-molecular research.

Homeopathy and its therapeutic principle ‘similia sibilibus curentur’, as well as ‘drug potentization’ could be rationally explained only with the help of supra-molecular chemistry.

The existence of intermolecular forces was first postulated by Johannes Diderik van der Waals in 1873. However, Nobel laureate Hermann Emil Fischer developed supra-molecular chemistry’s philosophical roots. In 1894, Hermann Emil Fischer suggested that enzyme-substrate interactions take the form of a “lock and key”, the fundamental principles of molecular recognition and host-guest chemistry. In the early twentieth century non-covalent bonds were understood in gradually more detail, with the hydrogen bond being described by Latimer and Rodebush in 1920.

The use of these principles gradually led to an increasing understanding of protein structure and other biological processes. For instance, the important breakthrough that allowed the elucidation of the double helical structure of DNA occurred when it was realized that there are two separate strands of nucleotides connected through hydrogen bonds. The use of non-covalent bonds is essential to replication because they allow the strands to be separated and used to template new double stranded DNA.

Eventually, chemists were able to take these concepts and apply them to synthetic systems. The breakthrough came in the 1960s with the synthesis of the crown ethers by Charles J. Pedersen. Following this work, other researchers such as Donald J. Cram, Jean-Marie Lehn and Fritz Vogtle became active in synthesizing shape- and ion-selective receptors, and throughout the 1980s research in the area gathered a rapid pace with concepts such as mechanically-interlocked molecular architectures emerging.

The importance of supra-molecular chemistry was established by the 1987 Nobel Prize for Chemistry which was awarded to Donald J. Cram, Jean-Marie Lehn, and Charles J. Pedersen in recognition of their work in this area. The development of selective “host-guest” complexes in particular, in which a host molecule recognizes and selectively binds a certain guest, was cited as an important contribution.

In the 1990s, supra-molecular chemistry became even more sophisticated, with researchers such as James Fraser Stoddart developing molecular machinery and highly complex self-assembled structures, and Itamar Willner developing sensors and methods of electronic and biological interfacing. During this period, electrochemical and photochemical motifs became integrated into supramolecular systems in order to increase functionality, research into synthetic self-replicating system began, and work on molecular information processing devices began. The emerging science of nanotechnology also had a strong influence on the subject, with building blocks such as fullerenes, nanoparticles, and dendrimers becoming involved in synthetic systems.

Supramolecular chemistry deals with subtle interactions, and consequently control over the processes involved can require great precision. In particular, noncovalent bonds have low energies and often no activation energy for formation. As demonstrated by the Arrhenius equation, this means that, unlike in covalent bond-forming chemistry, the rate of bond formation is not increased at higher temperatures. In fact, chemical equilibrium equations show that the low bond energy results in a shift towards the breaking of supramolecular complexes at higher temperatures.

However, low temperatures can also be problematic to supramolecular processes. Supramolecular chemistry can require molecules to distort into thermodynamically disfavored conformations, and may include some covalent chemistry that goes along with the supramolecular. In addition, the dynamic nature of supramolecular chemistry is utilized in many systems such as molecular mechanics, and cooling the system would slow these processes.

Thus, thermodynamics is an important tool to design, control, and study supra-molecular chemistry. Perhaps the most striking example is that of warm-blooded biological systems, which entirely cease to operate outside a very narrow temperature range.

The molecular environment around a supra-molecular system is also of prime importance to its operation and stability. Many solvents have strong hydrogen bonding, electrostatic, and charge-transfer capabilities, and are therefore able to become involved in complex equilibria with the system, even breaking complexes completely. For this reason, the choice of solvent can be critical.

‘Molecular self assembly’ is the construction of systems without guidance or management from an outside source other than to provide a suitable environment. The molecules are directed to assemble through non-covalent interactions. Self-assembly may be subdivided into intermolecular self-assembly to form a supramolecular assembly, and intra-molecular self-assembly or folding as demonstrated by foldamers and polypeptides. Molecular self-assembly also allows the construction of larger structures such as micelles, membranes, vesicles, liquid crystals, and is important to crystal engineering.

Molecular self-assembly is a key concept in supramolecular chemistry. This is because assembly of molecules in such systems is directed through noncovalent interactions such as hydrogen bonding, metal coordination, hydrophobic forces, van der Waals forces, pi-pi interactions,  as well as electromagnetic interactions. Common examples include the formation of micelles, vesicles, liquid crystal phases, and Langmuir monolayers by surfactant molecules. Further examples of supramolecular assemblies demonstrate that a variety of different shapes and sizes can be obtained using molecular self-assembly.

Molecular self-assembly allows the construction of challenging molecular topologies. One example is Borromean rings, interlocking rings wherein removal of one ring unlocks each of the other rings. DNA has been used to prepare a molecular analog of Borromean rings. More recently, a similar structure has been prepared using non-biological building blocks.

Molecular self-assembly underlies the construction of biologic macromolecular assemblies in living organisms, and so is crucial to the function of cells. It is exhibited in the self-assembly of lipids to form the membrane, the formation of double helical DNA through hydrogen bonding of the individual strands, and the assembly of proteins to form quaternary structures. Molecular self-assembly of incorrectly folded proteins into insoluble amyloid fibers is responsible for infectious prion-related neurodegenerative diseases. Molecular self-assembly of nanoscale structures plays a role in the growth of the remarkable β-keratin lamellae/setae/spatulae structures used to give geckos the ability to climb walls and adhere to ceilings and rock overhangs

DNA nanotechnology is an area of current research that uses the bottom-up, self-assembly approach for nanotechnological goals. DNA nanotechnology uses the unique molecular recognition properties of DNA and other nucleic acids to create self-assembling branched DNA complexes with useful properties. DNA is thus used as a structural material rather than as a carrier of biological information, to make structures such as two-dimensional periodic lattices (both tile-based as well as using the “DNA origami” method) and three-dimensional structures in the shapes of polyhedra. These DNA structures have also been used to template the assembly of other molecules such as gold nanoparticles and streptavidin proteins

Study of ‘molecular self assembly’ is very important in understanding molecular imprinting involved in homeopathic drug potentization.

‘Molecular recognition’ is the specific binding of a guest molecule to a complementary host molecule to form a ‘host-guest complex’. Often, the definition of which species is the “host” and which is the “guest” is arbitrary. The molecules are able to identify each other using non-covalent interactions. Key applications of this field are the construction of molecular sensors and catalysis.

Molecular recognition and self-assembly may be used with reactive species in order to pre-organize a system for a chemical reaction to form one or more covalent bonds. It may be considered a special case of supra-molecular catalysis. Non-covalent bonds between the reactants and a “template” hold the reactive sites of the reactants close together, facilitating the desired chemistry. This technique is particularly useful for situations where the desired reaction conformation is thermodynamically or kinetically unlikely, such as in the preparation of large macrocycles. This pre-organization also serves purposes such as minimizing side reactions, lowering the activation energy of the reaction, and producing desired stereochemistry. After the reaction has taken place, the template may remain in place, be forcibly removed, or may be “automatically” decomplexed on account of the different recognition properties of the reaction product. The template may be as simple as a single metal ion or may be extremely complex.

‘Mechanically-interlocked molecular architectures’ consist of molecules that are linked only as a consequence of their topology. Some non-covalent interactions may exist between the different components often those that were utilized in the construction of the system, but covalent bonds do not. Supramolecular chemistry, and template-directed synthesis in particular, is key to the efficient synthesis of the compounds. Examples of mechanically-interlocked molecular architectures include catenanes, rotaxanes, molecular knots, molecular Borromean rings and ravels.

In certain situations, ‘supra-molecular chemistry’ may include ‘covalent bondings’ also. In such  ‘dynamic covalent chemistry’, covalent bonds are broken and formed in a reversible reaction under thermodynamic control. While covalent bonds are key to the process, the system is directed by non-covalent forces to form the lowest energy structures

‘Biomimetics’ is an important application of supra-molecular chemistry. Many synthetic supra-molecular systems are designed to copy functions of biological systems. These bio-mimetic architectures can be used to learn about both the biological model and the synthetic implementation. Examples include photoelectrochemical systems, catalytic systems, protein design and self-replication.

‘Molecular imprinting’ is another application of supra-molecular chemistry, which describes a process by which a host is constructed from small molecules using a suitable molecular species as a template. After construction, the template is removed leaving only the host. The template for host construction may be subtly different from the guest that the finished host binds to. In its simplest form, imprinting utilizes only steric interactions, but more complex systems also incorporate hydrogen bonding and other interactions to improve binding strength and specificity.

Homeopathic potentization could be rationally explained by molecular imprinting.

‘Molecular machines’ are molecules or molecular assemblies derived from supramolecular chemistry, that can perform functions such as linear or rotational movement, switching, and entrapment. These devices exist at the boundary between supramolecular chemistry and nanotechnology, and prototypes have been demonstrated using supramolecular concepts

Different synthetic recognition motifs commonly utilized in supramolecular chemistry:  The ‘pi-pi charge-transfer interactions’ of bipyridinium with dioxyarenes or diaminoarenes have been used extensively for the construction of mechanically interlocked systems and in crystal engineering. The use of ‘crown ether binding’ with metal or ammonium cations is ubiquitous in supramolecular chemistry. The formation of ‘carboxylic acid dimers’ and other simple hydrogen bonding interactions. The complexation of bipyridines or tripyridines with ruthenium, silver or other metal ions is of great utility in the construction of complex architectures of many individual molecules. The complexation of porphyrins or phthalocyanines around metal ions gives access to catalytic, photochemical and electrochemical properties as well as complexation. These units are used a great deal by nature. ‘Macrocycles’ are also very useful in supramolecular chemistry, as they provide whole cavities that can completely surround guest molecules and may be chemically modified to fine-tune their properties. Cyclodextrins, calixarenes, cucurbiturils and crown ethers are readily synthesized in large quantities, and are therefore convenient for use in supramolecular systems. More complex cyclophanes, and cryptands can be synthesised to provide more tailored recognition properties. Supramolecular metallocycles are macrocyclic aggregates with metal ions in the ring, often formed from angular and linear modules. Common metallocycle shapes in these types of applications include triangles, squares, and pentagons, each bearing functional groups that connect the pieces via “self-assembly”. Metallacrowns are metallomacrocycles generated via a similar self-assembly approach from fused chelate-rings.

Many supramolecular systems require their components to have suitable spacing and conformations relative to each other, and therefore easily-employed structural units are required. Commonly used spacers and connecting groups include polyether chains, biphenyls and triphenyls, and simple alkyl chains. The chemistry for creating and connecting these units is very well understood. Nanoparticles, nanorods, fullerenes and dendrimers offer nanometer-sized structure and encapsulation units.

Surfaces can be used as scaffolds for the construction of complex systems and also for interfacing electrochemical systems with electrodes. Regular surfaces can be used for the construction of self-assembled monolayers and multilayers.

Photo-electro-chemically active units are used in supra-molecular chemistry. Porphyrins, and phthalocyanines have highly tunable photochemical and electrochemical activity as well as the potential for forming complexes. Photochromic and photoisomerizable groups have the ability to change their shapes and properties (including binding properties) upon exposure to light. TTF and quinones have more than one stable oxidation state, and therefore can be switched with redox chemistry or electrochemistry. Other units such as benzidine derivatives, viologens groups and fullerenes, have also been utilized in supramolecular electrochemical devices.

Certain ‘biologically-derived units’ are also utilized in supra-molecular chemistry. The extremely strong complexation between avidin and biotin is instrumental in blood clotting, and has been used as the recognition motif to construct synthetic systems. The binding of enzymes with their cofactors has been used as a route to produce modified enzymes, electrically contacted enzymes, and even photoswitchable enzymes. DNA has been used both as a structural and as a functional unit in synthetic supramolecular systems.

Applications of supramolecular chemistry is fastly expanding. Supramolecular chemistry and molecular self-assembly processes in particular have been applied to the development of new materials. Large structures can be readily accessed using bottom-up synthesis as they are composed of small molecules requiring fewer steps to synthesize. Thus most of the bottom-up approaches to nanotechnology are based on supramolecular chemistry.

A major application of supramolecular chemistry is the design and understanding of catalysts and catalysis. Noncovalent interactions are extremely important in catalysis, binding reactants into conformations suitable for reaction and lowering the transition state energy of reaction. Template-directed synthesis is a special case of supramolecular catalysis. Encapsulation systems such as micelles and dendrimers are also used in catalysis to create microenvironments suitable for reactions (or steps in reactions) to progress that is not possible to use on a macroscopic scale.

Supramolecular chemistry has been used to demonstrate computation functions on a molecular scale. In many cases, photonic or chemical signals have been used in these components, but electrical interfacing of these units has also been shown by supramolecular signal transduction devices. Data storage has been accomplished by the use of molecular switches with photochromic and photoisomerizable units, by electrochromic and redox-switchable units, and even by molecular motion. Synthetic molecular logic gates have been demonstrated on a conceptual level. Even full-scale computations have been achieved by semi-synthetic DNA computers.

Research in supramolecular chemistry also has application in green chemistry where reactions have been developed which proceed in the solid state directed by non-covalent bonding. Such procedures are highly desirable since they reduce the need for solvents during the production of chemicals.

Supramolecular chemistry is often pursued to develop new functions that cannot appear from a single molecule. These functions also include magnetic properties, light responsiveness, self-healing polymers, synthetic ion channels, molecular sensors, etc. Supramolecular research has been applied to develop high-tech sensors, processes to treat radioactive waste, and contrast agents for CAT scans.

Supramolecular chemistry is also important to the development of new pharmaceutical therapies by understanding the interactions at a drug binding site. The area of drug delivery has also made critical advances as a result of supramolecular chemistry providing encapsulation and targeted release mechanisms. In addition, supramolecular systems have been designed to disrupt protein-protein interactions that are important to cellular function. Supramolecular chemistry and molecular imprinting could be utilized in modern drug designing technology of next generation. Molecular imprinted water and biomolecules such as proteins are promising areas. It should be in this connection that we should study the MOLECULAR IMPRINTING perspective of homeopathic potentization, proposed by MIT concepts.


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