Evidence for ATP Interaction with Phosphatidylcholine Bilayers

García, Álvaro; Pochinda, Simon; Elgaard-Jørgensen, Paninnguaq Naja; Khandelia, Himanshu; Clarke, Ronald J.

doi:10.1021/acs.langmuir.9b01240

Cited by 8 publications

(9 citation statements)

References 58 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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“…Evidence suggests that a relationship exists between statin lipophilicity and pleiotropy, which supports the hypothesis that the effects of statins are dependent on where it resides within biological membranes [28][29][30]. It is known that the inclusion of amphiphiles into lipid bilayers impacts lipid bilayer parameters like permeability and thickness [104,105]. Moreover, amphiphilic drugs are soluble in aqueous biological fluids and can diffuse through the body, and partition into membranes [106,107].…”

Section: Statin-membrane Interactionsmentioning

confidence: 56%

The Role of Structure and Biophysical Properties in the Pleiotropic Effects of Statins

Murphy

Deplazes

Cranfield

et al. 2020

IJMS

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Statins are a class of drugs used to lower low-density lipoprotein cholesterol and are amongst the most prescribed medications worldwide. Most statins work as a competitive inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGR), but statin intolerance from pleiotropic effects have been proposed to arise from non-specific binding due to poor enzyme-ligand sensitivity. Yet, research into the physicochemical properties of statins, and their interactions with off-target sites, has not progressed much over the past few decades. Here, we present a concise perspective on the role of statins in lowering serum cholesterol levels, and how their reported interactions with phospholipid membranes offer a crucial insight into the mechanism of some of the more commonly observed pleiotropic effects of statin administration. Lipophilicity, which governs hepatoselectivity, is directly related to the molecular structure of statins, which dictates interaction with and transport through membranes. The structure of statins is therefore a clinically important consideration in the treatment of hypercholesterolaemia. This review integrates the recent biophysical studies of statins with the literature on the physiological effects and provides new insights into the mechanistic cause of statin pleiotropy, and prospective means of understanding the cholesterol-independent effects of statins.

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“…This could be explained by K + bridging between PEO and the phosphate group of dUTP since it was shown that ATP associates with DOPC bilayers. [ 49 ] These membrane interactions led to heterogeneous distribution of FITC‐12‐d‐UTP (Figure 6D and Figures S34 and S35, Supporting Information) and often resulted in tight contacts between the GUVs and formation of tissue‐like structure (Figure S36, Supporting Information).…”

Section: Resultsmentioning

confidence: 99%

Fusion‐Induced Growth of Biomimetic Polymersomes: Behavior of Poly(dimethylsiloxane)‐Poly(ethylene oxide) Vesicles in Saline Solutions Under High Agitation

Marušič

Zhao

Otrin

et al. 2021

Macromol. Rapid Commun.

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Giant unilamellar vesicles serve as membrane models and primitive mockups of natural cells. With respect to the latter use, amphiphilic polymers can be used to replace phospholipids in order to introduce certain favorable properties, ultimately allowing for the creation of truly synthetic cells. These new properties also enable the employment of new preparation procedures that are incompatible with the natural amphiphiles. Whereas the growth of lipid compartments to micrometer dimensions has been well established, growth of their synthetic analogs remains underexplored. Here, the influence of experimental parameters like salt type/concentration and magnitude of agitation on the fusion of nanometer‐sized vesicles made of poly(dimethylsiloxane)‐poly(ethylene oxide) graft copolymer (PDMS‐g‐PEO) is investigated in detail. To this end, dynamic light scattering, microscopy, and membrane mixing assays are employed, and the process at different time and length scales is analyzed. This optimized method is used as an easy tool to obtain giant vesicles, equipped with membrane and cytosolic biomachinery, in the presence of salts at physiological concentrations.

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Evidence for ATP Interaction with Phosphatidylcholine Bilayers

Cited by 8 publications

References 58 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

The Role of Structure and Biophysical Properties in the Pleiotropic Effects of Statins

Fusion‐Induced Growth of Biomimetic Polymersomes: Behavior of Poly(dimethylsiloxane)‐Poly(ethylene oxide) Vesicles in Saline Solutions Under High Agitation

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