Light, Water, and Melatonin Relationship with Hydrogen Bonds: History
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Contributor:
Doris Loh

The synergistic relationship between melatonin, water, and light may have originated billions of years ago when primitive unicellular organisms depended on this effective and precise synergy to modulate phase separation to control protein aggregation and associated biological effects. The efficacy of this synergy also provides a credible explanation for the immensely successful and rapid distribution of melatonin via horizontal gene transfer. The discovery of the serotonin N-acetyltransferase (SNAT) gene responsible for the synthesis of essential melatonin substrate N-acetylserotonin (NAS) in archaea firmly establishes the quintessential role played by melatonin in early primitive organisms that use phase separation as the fundamental driver for relevant biochemical and biophysical processes to support metabolism, replication, and survival.

  • melatonin
  • dementia
  • light
  • viscosity

1. Introduction

Melatonin (N-acetyl-5-methoxytryptamine) was first isolated from bovine pineal gland in 1958 [1]. Since then, revelations from the study of melatonin led to a continuously expanding list of appellations that aim to describe its impressive yet often pleiotropic and contradictory behaviors. Melatonin is known as a hormone, an antioxidant, an anticancer agent, an antiviral, an autocoid, a chronobiotic, a hypnotic, an anxiolytic, a glycolytic, a sleep aid, a universal panacea, a biological modifier, and even a Higgs boson [2]. These nomenclatures are excellent illustrations of some of the broad-based metabolic effects achieved by melatonin as it regulates fundamental phase separation processes in living organisms. The role of melatonin in the regulation of phase separation in the context of neurodegenerative disorders, cancer multidrug resistance, and viral phase separation are clearly defined in several in-depth reviews [3][4][5]. Due to a limitation of scope, the reader may review these extensive discussions for a better understanding of molecular mechanisms employed by melatonin in the regulation of phase separation under different biological contexts. 

2. Hydrogen Bonds Modulate Viscosity

Intrinsically, phase separation is entropically unfavorable and driven predominantly by enthalpically favored protein interactions [6][7][8]. Limited hydration in the interior of membraneless organelles fosters a favorable environment for liquid-to-solid phase transitions observed in amyloidogenic aggregates that are often preceded by liquid-to-liquid phase separation [9][10]. In other words, desolvation or the release of water molecules from protein hydration shells into bulk water [11][12][13] create entropic gains that promote phase separation and fibril aggregation [14][15][16]. During α-syn nucleation, limited hydration lowers the desolvation barrier and intermolecular hydrogen bond barrier. Thus, the simple removal of confined water molecules in the hydrophobic amyloid NAC domain in α-syn can easily breach high desolvation barriers that normally prevent aggregation of amyloid fibrils [17][18][19]. Consequently, the ability to manipulate the relative thermodynamics of hydrogen bonds [20] in interfacial water compared to bulk becomes an extremely attractive proposition in the regulation of protein aggregation induced by phase separation.

Water molecules confined in interfacial hydration water exhibit severely restrained mobility compared to bulk water [21]. The mobility of these water molecules is reduced by interfacial viscosities as high as 106 times that of bulk [22][23]. However, the viscosity of water constrained in extremely narrow spaces such as the interior of carbon nanotubes increases and decreases with increased and decreased diameters, respectively [24][25]. In carbon nanotubes with diameters below 20 Å, water stops behaving like bulk water with different boiling points, self-diffusion coefficient, and viscosity [24][26][27][28]. Even the mobility of water molecules in ultra-confined spaces is enhanced by reduced viscosity [25][29] which is facilitated by a reduction in hydrogen bonds.
In general, viscosity is increased by stronger intermolecular interactions that form more hydrogen bonds in water molecules [24]. During phase separation, the variation in internal micro-viscosity between tau droplets formed via homotypic and heterotypic associations can be as much as a 7-fold increase [30]. Systematic reductions in droplet micro-viscosity during biological aging may imply continuously evolving intermolecular interactions that shift droplet equilibrium, modifying aggregation potential that favor pathological outcomes [31][32][33]. Therefore, novel properties such as enhanced solubility, diffusion, and electron transfer in specially treated water molecules with lower viscosity and reduced/broken hydrogen bonds [34] may have distinctive effects on the modulation of aberrant protein aggregation in dementia.
Hydrogen bonds (HBs) can be reduced/broken by hot electron transfer when plain, deionized bulk water is allowed to flow through gold nanoparticles under resonant illumination. The water—known as plasmon-activated water (PAW)—created by this method exhibits features conspicuously different from bulk even at room temperature [34]. The reduced intermolecular hydrogen bonds in water molecules not only decrease viscosity, but also impart a higher degree of freedom in interaction that allows the formation of stronger intermolecular hydrogen bonding with hydrophilic solutes while enhancing the solubility of hydrophobic solutes [34][35]. Essentially, the elevated interactions with other molecules via increased free water molecules in PAW enhance the intrinsic activities of these molecules. Melatonin is known to dissolve poorly in water [36]; however, melatonin is able to form stronger hydrogen bonds in PAW resulting in enhancement of solubility between ~120% [35] to ~150% [37].

3. PAW Modulates Melatonin Hydrogen Bonding and Conformation

Melatonin has five distinct hydrogen bonding sites for water, forming up to five hydrogen bonds with water molecules simultaneously at varying strengths. Two of these hydrogen molecules from two water molecules can even reside indefinitely when they are coordinated with the O of the amide group due to the high degree of stability between the H-bond as indicated by Helmholtz free energy [38][39]. For melatonin, water can either be a H-bond donor or acceptor, depending on the site it is attached to. However, even one single water molecule attached to melatonin can change its conformational preference by modulating the relative energies of the conformations and the heights of the barriers that separate conformations, where strong H-bonds can produce substantial electronic frequency shifts. Furthermore, the relative abundance of the conformations can also be regulated by H-bonds, implying that preferential binding between specific sites and water molecules can produce conformational clusters with populations as high as 10 times over other species [39]. In bulk water, melatonin forms the strongest H-bond with its carbonyl O group, stabilizing its tendency to self-aggregate resulting in low solubility [40].
Melatonin prepared in PAW compared to bulk deionized water exhibited enhanced clearance of hydroxyl radical at 11.9% vs. 6.69%, respectively; its antiviral potency against dengue virus in infected human hepatocarcinoma cells is also enhanced, reducing infectivity by 14.7% vs. 20.6% in bulk [37]. Male Wistar rats subjected to chronic sleep deprivation (CSD) using the disc-on-water methodology [41] and treated with 10 mg/kg melatonin via intraperitoneal (IP) injection dissolved in PAW exhibited significantly better results in all parameters detected, including hepatic function and metabolic activity, than control (no treatment), CSD only, and CSD + melatonin dissolved in bulk deionized water groups [37]. It is plausible that when melatonin is dissolved in PAW, the intrinsic anti-inflammatory properties of PAW may also be responsible for molecular mechanisms that support/enhance melatonin’s antiviral and antioxidative features. Indeed, APP/PS1 transgenic AD mice treated with PAW showed improved memory function and reduced amyloid burden, potentially via anti-inflammatory and anti-oxidative effects, compared to age-matched wild-type controls [42][43]. There is no doubt that the anti-oxidative properties of PAW enhance melatonin’s intrinsic activities. However, the molecular mechanism involved is an unexpected, viscous one.

4. Reactive Oxygen Species Increase Viscosity

Hydrophilicity enhances viscosity in interfacial water at values up to ~106 times that of bulk due to an increase in ordering and hydrogen-bond dynamics [22]. The negative polarity of reactive oxygen species (ROS) is able to increase hydrophilicity and elevate viscosity. When the oxygen atom of one of the most reactive ROS hydroxyl radical (•OH) becomes highly negative and acts as a hydrogen bond acceptor, it can lower the reaction barrier stabilizing •OH bonding to water during the polar transition state. Thus, water and viscosity of water can modulate and stabilize the highly reactive •OH [44]. In bulk water, •OH forms three stable hydrogen bonds and a weaker hemibond with surrounding water molecules comprising its solvation shell [45].
In mitochondria, •OH is derived from superoxide radicals produced as a result of a one-electron reduction of oxygen (O2) from electron leakage during mitochondrial electron transport [46][47]. Simply stated, the presence of excess, unneutralized ROS can significantly elevate viscosity in these essential energy-producing organelles, negatively impacting mitochondrial functions and adenosine triphosphate (ATP) production associated with pathological Aβ aggregation [48]. Hydrogen peroxide (H2O2)—a ubiquitous ROS with classical intracellular signaling functions at lower physiological levels [49]—is also produced in mitochondria from electrons leaked during mitochondrial electron transport activities [46]. Similar to •OH, H2O2 accumulation can increase matrix viscosity in mitochondria [50][51]. Furthermore, an NIR emissive fluorescent probe with a large Stokes shift detected significantly elevated viscosity and H2O2 levels in brain mitochondria of APP/PS1 transgenic AD mice compared to normal BALB/c mice [52].

5. Reduction in Viscosity and Hydrogen Bonds Enhance Melatonin ROS Scavenging

Melatonin is known for its ability to scavenge •OH and other free radicals [53][54][55][56][57] where one molecule of melatonin can scavenge two •OH radicals to produce the stable cyclic 3-hydroxymelatonin (3-OHM) metabolite [53]. However, the addition of only one water molecule that provides an H-bonding relay pathway significantly lowered the energy barrier in the tautomerization step to enhance the scavenging potential by melatonin [58]. The fact that melatonin prepared in PAW exhibit 78% increased effectiveness in •OH scavenging compared to bulk (11.9% vs. 6.69%) [37] implies that melatonin may adopt more favorable conformations that enhance its intrinsic activities as a result of stronger H-bonds formed in water with reduced viscosity and H-bonds compared to bulk.
In the context of aberrant protein aggregation in dementia, the signature reduction in viscosity and H-bonds in PAW inadvertently accentuates an unconventional but relevant perspective on the viscous relationships between light, melatonin, and ROS that surprisingly, or not, converge on the synthesis of ATP in mitochondria. In response to conditions that reduce ATP, budding yeast conserves energy by increasing cytosolic viscosity to slow cellular processes by reducing protein diffusion rates. Additionally, increased viscosity modulates phase separation, impeding the formation of stress granules and inducing aberrant phase separation to form aggregates that were not present in cells that could not elevate viscosity [59].

6. Light Reduces Viscosity and Hydrogen Bonds to Increase ATP Production in Mitochondria

The ability to increase ATP production in mitochondria is one of the most widely accepted mechanisms behind the effectiveness of photobiomodulation employing visible red light (670 nm), non-visible near infrared (NIR, 800–1090 nm), and even far infrared (FIR, 3–25 µm) in dementia and other health challenges [60][61][62][63][64]. The fact that both infrared light and melatonin increase ATP production, and the adenosine moiety of ATP which is structurally similar to melatonin is capable of solubilizing protein aggregation point to the existence of a most unexpected, dynamic relationship between light and melatonin that is inextricably connected to the regulation of hydrogen bonds, viscosity, protein hydration, and protein aggregation.

Although improved ATP production and reduced ROS production are associated with the use of 670 nm irradiation, the exact mechanism responsible for these effects remains controversial. Experimental works employing 670 nm report the reduction in inflammation via increased expression of cytochrome C oxidase (COX) under various conditions [65] [66] [67][68]. COX is generally viewed as the primary photoacceptor in mitochondria. However, molecular mechanisms that elucidate the association of irradiation by 710–790 nm and 650–680 nm wavelengths with reduced and oxidized states of COX, respectively, remain elusive [69].

Experimental work that combined nanoindentation and 670 nm laser irradiation to modulate viscosities of interfacial water supports the proposal that lower viscosity in mitochondria is the real driver behind photobiomodulation propelling enhanced ATP synthesis, and not increased COX expression and activities [70][71][72]. The higher viscosity of the medium can slow down the rotation of the F1 motor to reduce ATP synthesis not only in mitochondria [73] but also chloroplasts [74]. While ATPase turnover rates are more effective when detected by probes designed with lower viscous drag [75], viscous drag can dramatically slow the rate of rotation to 3% of the enzyme turnover rate in Escherichia coli [76]. Nonetheless, 100% efficiency of the F1 rotor can theoretically be achieved if the 120° power strokes rotate at a constant angular velocity [77]. However, power stroke and dwell duration are easily modified by viscosity.

Viscous loads applied to the ATP F1 motor of E. coli can cause the increase in the duration of the 120° power stroke that is correlated to a 20-fold increase in the length of the dwell. Thus, the power stroke velocity is limited by the viscous load on the motor, and consequently, increases in transition time are the direct result of increases in viscosity and not from inhibition of the ATPase by other means [78]. A deeper analysis of viscosity sensitivity showed that viscous drag on rotations of the γ-subunit in the F1 motor [79] can cause variations of more than 5000-fold by using a variety of rotation probes [80]. However, if reduced viscosity from light irradiation is responsible for increased ATP synthesis via increased power stroke velocity producing more efficient F1 motor rotations, then this proposal should be inclusive of COX involvement because the main activity of COX—the oxidation of ferricytochrome C by COX—is also viscosity-dependent [81][82]. Therefore, by reducing viscosity and hydrogen bonds, light increases ATP production in mitochondria not only via enhanced COX activity but also efficiency of ATP synthase rotation.

7. Conclusion

Visible 670 nm red light reduces hydrogen bonds and viscosity in mitochondria interfacial water to increase free water molecules and enhance ATP synthase ability to generate more ATP. ROS increase viscosity and lower ATP synthase efficiency to inhibit ATP production. Melatonin lowers viscosity by scavenging •OH and ROS. Increased free water molecules from lower viscosity form stronger hydrogen bonds with melatonin to enhance its intrinsic features that include binding interactions with the adenosine moiety of ATP, inhibiting water removal from protein hydration shells that facilitate amyloid fibril aggregation and solubilizing aggregates formed as the result of aberrant phase separation. Light, water, and melatonin constitute an ancient synergy that ensures adequate protein hydration to prevent aberrant phase separation.

This entry is adapted from the peer-reviewed paper 10.3390/ijms24065835

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