The effects of melatonin, serotonin, tryptophan and NAS on the biophysical properties of DPPC monolayers

Robinson, Morgan; Turnbull, Stephen J.; Lee, Brenda Yasie; Leonenko, Zoya

doi:10.1016/j.bbamem.2020.183363

Cited by 19 publications

(10 citation statements)

References 57 publications

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“…Tryptophan [376][377][378], Glycine [139,284], Glutamate [139], Aginine [379], Alanine [379], 5-aminolevulinic acid and its esters [380], L-dopa [138,199,381,382] Nucleotides ATP [383], UMP [384], DNA [385], ADOMET [381] Sugars and carbohydrates Trehalose [386], Gastrodin [387], Mannitol [199], 1,3,7-trimethyluric acid [388] Neurotransmitters Dopamine [138,[389][390][391][392][393][394][395][396][397], Serotonin [138,378,389,396,[398][399][400][401][402], Adenosine [138], Melatonin [138,229,378,389,[403][404]…”

Section: Antioxidantsmentioning

confidence: 99%

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

2021

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We review the use of molecular dynamics (MD) simulation as a drug design tool in the context of the role that the lipid membrane can play in drug action, i.e., the interaction between candidate drug molecules and lipid membranes. In the standard “lock and key” paradigm, only the interaction between the drug and a specific active site of a specific protein is considered; the environment in which the drug acts is, from a biophysical perspective, far more complex than this. The possible mechanisms though which a drug can be designed to tinker with physiological processes are significantly broader than merely fitting to a single active site of a single protein. In this paper, we focus on the role of the lipid membrane, arguably the most important element outside the proteins themselves, as a case study. We discuss work that has been carried out, using MD simulation, concerning the transfection of drugs through membranes that act as biological barriers in the path of the drugs, the behavior of drug molecules within membranes, how their collective behavior can affect the structure and properties of the membrane and, finally, the role lipid membranes, to which the vast majority of drug target proteins are associated, can play in mediating the interaction between drug and target protein. This review paper is the second in a two-part series covering MD simulation as a tool in pharmaceutical research; both are designed as pedagogical review papers aimed at both pharmaceutical scientists interested in exploring how the tool of MD simulation can be applied to their research and computational scientists interested in exploring the possibility of a pharmaceutical context for their research.

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Section: Antioxidantsmentioning

confidence: 99%

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

2021

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“…[21][22][23][24][25] It has also been shown that isothermal compressibility of lipid monolayers can be alteredb ys mall serotonin-related molecules (such as melatonin) at % 1mm concentration, and even by serotonin at higher concentrations. [26] Furthermore, serotonin binding to raft-like mixed model membranes was shown to alter domain size. [27,28] If serotonin also changes the mechanical properties of the bilayer, then that in turn can affect cellular functions, including membrane protein function, membrane affinity of other molecules as ap rerequisite for subsequent receptor binding, and key cellular processes such as exocytosis and endocytosis.…”

Section: Introductionmentioning

confidence: 99%

Altered Membrane Mechanics Provides a Receptor‐Independent Pathway for Serotonin Action

Dey

Surendran

Engberg

et al. 2021

Chemistry A European J

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Serotonin, an importants ignalingm olecule in humans, has an unexpectedly high lipid membrane affinity. The significance of this finding has evokedc onsiderable speculation. Here we show that membrane binding by serotonin can directly modulate membrane properties and cellular function, providing an activity pathway completelyi ndependent of serotonin receptors. Atomic force microscopy shows that serotonin makes artificial lipid bilayers softer,a nd inducesn ucleation of liquid disordered domains inside the raft-likel iquid-ordered domains. Solid-state NMR spectrosco-py corroborates this data at the atomic level,r evealing ah omogeneous decrease in the order parameter of the lipid chainsi nt he presence of serotonin. In the RN46A immortalized serotonergicn euronal cell line, extracellular serotonin enhances transferrin receptor endocytosis, even in the presence of broad-spectrum serotonin receptor and transporter inhibitors. Similarly,i ti ncreases the membrane binding and internalizationo fo ligomeric peptides. Our resultsu ncover a mode of serotonin-membrane interaction that can potentiate key cellular processes in ar eceptor-independent fashion.

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“…More recently, also allosteric regulation pathways leading to functional selectivity have been described through which small molecules interact with their targets (Macpherson and Anastasiou, 2017). Both biologically and pharmacologically active compounds are often lipophilic and, especially when administered in relatively high dose that can reach a few mol% (Bruns et al, 2000), may unspecifically interact with the cellular membrane (Postila et al, 2016;Josey et al, 2020;Turnbulla et al, 2020). Binding of small lipophilic molecules to membranes is described by a partition equilibrium and can lead to substantial accumulation of the respective compound.…”

Section: Introductionmentioning

confidence: 99%

“…5-HT has been known to partition into the lipid water interface of model membranes altering membrane structure and lipid packing (Yau et al, 1998;Peters et al, 2013). The octanol/water partition coefficient (log P) of 5-HT has been determined to be between 0.56 and 0.73 indicating its lipophilic potential (Postila et al, 2016;Turnbulla et al, 2020). Indeed, also MD simulations hinted to its membrane binding preference, 84% of the 5-HT was found membrane-bound (Postila et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Serotonin Alters the Phase Equilibrium of a Ternary Mixture of Phospholipids and Cholesterol

et al. 2020

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Unsaturated and saturated phospholipids tend to laterally segregate, especially in the presence of cholesterol. Small molecules such as neurotransmitters, toxins, drugs etc. possibly modulate this lateral segregation. The small aromatic neurotransmitter serotonin (5-HT) has been found to bind to membranes. We studied the lipid structure and packing of a ternary membrane mixture consisting of palmitoyl-oleoylphosphatidylcholine, palmitoyl-sphingomyelin, and cholesterol at a molar ratio of 4/4/2 in the absence and in the presence of 5-HT, using a combination of solid-state 2 H NMR, atomic force microscopy, and atomistic molecular dynamics (MD) simulations. Both NMR and MD report formation of a liquid ordered (L o) and a liquid disordered (L d) phase coexistence with small domains. Lipid exchange between the domains was fast such that single component 2 H NMR spectra are detected over a wide temperature range. A drastic restructuring of the domains was induced when 5-HT is added to the membranes at a 9 mol% concentration relative to the lipids. 2 H NMR spectra of all components of the mixture showed two prominent contributions indicative of molecules of the same kind residing both in the disordered and the ordered phase. Compared to the data in the absence of 5-HT, the lipid chain order in the disordered phase was further decreased in the presence of 5-HT. Likewise, addition of serotonin increased lipid chain order within the ordered phase. These characteristic lipid chain order changes were confirmed by MD simulations. The 5-HTinduced larger difference in lipid chain order results in more pronounced differences in the hydrophobic thickness of the individual membrane domains. The correspondingly enlarged hydrophobic mismatch between ordered and disordered phases is assumed to increase the line tension at the domain boundary, which drives the system into formation of larger size domains. These results not only demonstrate that small membrane binding molecules such as neurotransmitters have a profound impact on essential membrane properties. It also suggests a mechanism by which the interaction of small molecules with membranes can influence the function of membrane proteins and non-cognate receptors. Altered membrane properties may modify lateral sorting of membrane protein, membrane protein conformation, and thus influence their function as suspected for neurotransmitters, local anesthetics, and other small drug molecules.

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The effects of melatonin, serotonin, tryptophan and NAS on the biophysical properties of DPPC monolayers

Cited by 19 publications

References 57 publications

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

Altered Membrane Mechanics Provides a Receptor‐Independent Pathway for Serotonin Action

Serotonin Alters the Phase Equilibrium of a Ternary Mixture of Phospholipids and Cholesterol

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