Energy Medicine: Focus on Nonthermal Electromagnetic Therapies
Len Wisneski in The Scientific Basis of Integrative Health, 2017
Standard biochemical models cannot explain the behavior of all the regulation and control processes in physiology because of the extraordinary properties of biological tissues, such as the extremely high capability for electrical polarization at cell membranes, the high degrees of cooperativity (which imply very low degrees of freedom), and yet a very high flexibility of response. Cooperativity is the interaction process by which binding of a ligand to one site on a macromolecule influences binding at subsequent sites; it can even cause a conformational change in one subunit of a protein to be transmitted to all others. These cooperative effects could be expected to reduce the degrees of freedom (i.e., the possible number of different molecular interactions) for molecules. Yet, biochemical regulation processes exhibit wide ranges of fine-grained control. Similarly, simple equilibrium physics is insufficient to characterize the more subtle metabolic processes, such as electromagnetic wave propagation in living tissues or large-scale biological rhythms.
Carriage of Oxygen in Blood
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal in Principles of Physiology for the Anaesthetist, 2020
In the erythrocyte, haemoglobin is folded into a complex, convoluted shape with the haem enclosed in a cleft formed by the protein, forming loose bonds with amino acids within the globin chain. Haemoglobin can exist in two structural forms, the tense (T) form and the relaxed (R) form. The difference between the two forms is brought about by a slight rotation of one pair of subunits with respect to the other. Oxygen binds about 70 times more easily to haem in the relaxed form than in the tense form. As more haems bind to oxygen, the transition to the relaxed state occurs more readily and the affinity for O2 increases. Hence, as haemoglobin binds O2, the binding of further O2 molecules becomes easier until four O2 molecules have been bound, at which point the haemoglobin is saturated (Adair equation). The final stage of oxygenation (i.e. binding of the fourth O2 molecule) is substantially faster than the previous three. This is known as positive cooperativity. The conformation of the haemoglobin molecule is altered by physical and chemical factors (including temperature, hydrogen ion concentration, carbon dioxide and 2,3-diphosphoglycerate concentration). Such physicochemical factors can therefore change the affinity of haemoglobin for oxygen.
Kinetic Theory
Clive R. Bagshaw in Biomolecular Kinetics, 2017
If and, hence, , but and , then the sites are identical but interacting (cooperative) such that binding of one molecule of L to either site changes the structure of the other site to affect the binding of the second molecule. If , when expressed as association equilibrium constants, then the reaction shows positive cooperativity in that binding of the first ligand at either site favors tighter binding of the second ligand at the remaining site (Figure 2.21). An equilibrium titration shows a sigmoid curve (Figure 2.21c) as discussed in Section 4.6. If , binding of the first ligand inhibits binding of the second ligand, so-called negative cooperativity. This titration profile gives a biphasic hyperbolic function, similar to the case where the second site is inherently weaker, because the two species, LP and PL, are not normally distinguishable. Finally, in the case of inherently different sites that interact, all four equilibrium constants may be different, but to maintain thermodynamic balance.
A molecular perspective on identifying TRPV1 thermosensitive regions and disentangling polymodal activation
Published in Temperature, 2023
Dustin D. Luu, Aerial M. Owens, Mubark D. Mebrat, Wade D. Van Horn
In the concatemer and other studies, a Hill model of cooperativity can be used to assess the allosteric implications between multiple ligand-binding sites [189]. A Hill coefficient (Kd) for additional oxygen-binding molecules [190]. Highly positive cooperative events, like found in hemoglobin, will generally have minimal intermediate bound states with an “all or nothing” binding process. In the context of hemoglobin, which is exceptionally cooperative, it is typically found in either an unbound or fully bound state [191]. Conversely, negative cooperativity functions to decrease the affinity of ligand binding as more ligands bind the substrate. The outcomes of negative cooperativity are more populated and longer-lasting intermediate bound states [191]. A noncooperative process effectively has independent binding sites [191]. Analysis of the rTRPV1–CAP concatemer study identifies a Hill coefficient near unity, indicating that CAP activation is noncooperative. This appears to agree with the conclusion that CAP binding to a single subunit can fully open rTRPV1 [180]. In contrast, rTRPV1 concatemer proton activation exhibits positive cooperativity (4,180]. The reported differences in cooperativity between CAP and protons shines a light on mechanistically distinct TRPV1 activation modes and provide a vignette into the complexity of deciphering the polymodal crosstalk between activation modes.
Insights into the operational model of agonism of receptor dimers
Published in Expert Opinion on Drug Discovery, 2022
There are two kinds of dimers (Figure 1). Homodimers (Figure 1, left) consist of two identical receptors R for which a given agonist A has the same affinity (1/KA) and exerts the same operational efficacy τ. Two molecules of an agonist bound to two orthosteric binding sites exert allosteric interaction. The factor of binding cooperativity α quantifies the change in agonist affinity upon binding of the second molecule of agonist to the dimer. In the case of positive cooperativity, the affinity of two concurrently bound agonists is greater than the affinity of a single bound agonist and the value of binding cooperativity factor α is higher than 1. In the case of negative cooperativity, the affinity of two concurrently bound agonist molecules is smaller than the affinity of a single bound molecule and the value of binding cooperativity factor α is lower than 1. The change in operational efficacy τ upon binding of the second molecule of agonist to the dimer is quantified by efficacy cooperativity factor β. In analogy to binding cooperativity, values of β higher than 1 denote positive cooperativity leading to an increase in operational efficacy τ and values lower than 1 denote negative cooperativity leading to a decrease in τ.
The P50 value detected by the oxygenation-dissociation analyser and blood gas analyser
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2020
Zongtang Chu, Ying Wang, Guoxing You, Quan Wang, Ning Ma, Bingting Li, Lian Zhao, Hong Zhou
To date, two types of equipment have been used to obtain P50 values. Blood gas analysers are frequently used in the clinics to detect and export many parameters about blood, including P50 values. However, P50 values exported by blood gas analysers need further clarification. In addition, P50 values can be detected via spectrophotometric methods [25]. The ODC of haemoglobin was recorded using a UV-V spectrophotometer. Deoxygenated haemoglobin was obtained by repeated evacuations and flushing with argon gas (99.99%). A small amount of air was added gradually to deoxygenated haemoglobin before measuring absorption spectra from 450 to 650 nm. The P50 value and Hill’s cooperativity coefficient (n value) were then calculated from ODC and Hill plots, respectively [26]. Oxygenation-dissociation analysers are based on the above principles and specially designed to detect P50 values and parameters reflecting oxygen affinity. This method, however, is not easy to perform; it has only been used in research laboratories, and not been implemented clinically [27].
Related Knowledge Centers
- Binding Site
- DNA
- Enzyme
- Ligand
- Oxygen
- Phospholipid
- Protein
- Hemoglobin
- Receptor
- Cooperative Binding