Liposomal drug transport: A molecular perspective from molecular dynamics simulations in lipid bilayers

Xiang, Tian‐Xiang; Anderson, Bradley D.

doi:10.1016/j.addr.2006.09.002

Cited by 140 publications

(141 citation statements)

References 101 publications

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“…In general, it is interesting that the (extended) polar/ apolar interface appears to be the preferential location for most molecules interacting with lipid bilayers [64,87,88]. As already pointed out elsewhere [20], this observation may be rationalized considering the intramembrane pressure distribution, also known as the lateral pressure profile.…”

Section: Discussionmentioning

confidence: 85%

“…In fact, it will be seen that the statistical errors in the final average values are relatively small (figures 2 and 3). Incidentally, the sampling time attainable by standard fully atomistic z-constraint simulations [61][62][63][64] is typically 1 -2 orders of magnitude shorter than that achieved here thanks to our dual-resolution method. All z-constraint simulations presented in this work could be run almost concurrently on a supercomputer (www.southampton.ac.uk/ isolutions/computing/hpc/iridis).…”

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confidence: 99%

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Dual-resolution molecular dynamics simulation of antimicrobials in biomembranes

Orsi

Noro

Essex

2010

J. R. Soc. Interface.

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Triclocarban and triclosan, two potent antibacterial molecules present in many consumer products, have been subject to growing debate on a number of issues, particularly in relation to their possible role in causing microbial resistance. In this computational study, we present molecular-level insights into the interaction between these antimicrobial agents and hydrated phospholipid bilayers (taken as a simple model for the cell membrane). Simulations are conducted by a novel 'dual-resolution' molecular dynamics approach which combines accuracy with efficiency: the antimicrobials, modelled atomistically, are mixed with simplified (coarse-grain) models of lipids and water. A first set of calculations is run to study the antimicrobials' transfer free energies and orientations as a function of depth inside the membrane. Both molecules are predicted to preferentially accumulate in the lipid headgroup -glycerol region; this finding, which reproduces corresponding experimental data, is also discussed in terms of a general relation between solute partitioning and the intramembrane distribution of pressure. A second set of runs involves membranes incorporated with different molar concentrations of antimicrobial molecules (up to one antimicrobial per two lipids). We study the effects induced on fundamental membrane properties, such as the electron density, lateral pressure and electrical potential profiles. In particular, the analysis of the spontaneous curvature indicates that increasing antimicrobial concentrations promote a 'destabilizing' tendency towards non-bilayer phases, as observed experimentally. The antimicrobials' influence on the self-assembly process is also investigated. The significance of our results in the context of current theories of antimicrobial action is discussed.

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Section: Discussionmentioning

confidence: 85%

mentioning

confidence: 99%

Dual-resolution molecular dynamics simulation of antimicrobials in biomembranes

Orsi

Noro

Essex

2010

J. R. Soc. Interface.

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“…In recent years, standard atomic-level (AL) molecular dynamics simulations have indeed been successfully employed to predict permeability coefficients and to investigate the general mechanism of passive transport across membranes. 2,8,9 These investigations have been extremely useful in understanding many aspects of bilayer permeation with atomic resolution. However, the huge computational cost of simulating AL membrane models causes a number of problems.…”

Section: Introductionmentioning

confidence: 99%

“…1 For example, drug permeation is crucial to bioavailability, and is at the basis of the technology of liposomal transport systems. 2 Although important permeation mechanisms, such as those responsible for the translocation of sugars and amino acids, are actively controlled by proteins, passiVe permeation is the most common way by which solutes cross cell membranes. Most small molecules (such as water) and drugs are passively transported.…”

Section: Introductionmentioning

confidence: 99%

Permeability of Small Molecules through a Lipid Bilayer: A Multiscale Simulation Study

2009

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The transmembrane permeation of eight small (molecular weight <100) organic molecules across a phospholipid bilayer is investigated by multiscale molecular dynamics simulation. The bilayer and hydrating water are represented by simplified, efficient coarse-grain models, whereas the permeating molecules are described by a standard atomic-level force-field. Permeability properties are obtained through a refined version of the z-constraint algorithm. By constraining each permeant at selected depths inside the bilayer, we have sampled free energy differences and diffusion coefficients across the membrane. These data have been combined, according to the inhomogeneous solubility-diffusion model, to yield the permeability coefficients. The results are generally consistent with previous atomic-level calculations and available experimental data. Computationally, our multiscale approach proves 2 orders of magnitude faster than traditional atomic-level methods.

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“…It has been adopted in theoretical studies of biological membrane models (Tieleman et al 1997;Mark 2010, 2012) and partitioning and interaction of drugs in lipid bilayers (Fuchs et al 1990;Omote and Al-Shawi 2006;MacCallum and Tieleman 2006;Bemporad et al 2004). Indeed, MD simulations have contributed significantly to the understanding of the structure, dynamics and effects of biological molecules in lipid bilayers (Seydel and Wiese 2002;Xiang and Anderson 2006;Yamamoto et al 2012;Rissanen et al 2014;Almeida et al 2017). However, due to the variety of classical force fields available, it is important to compare the results obtained from the simulations with the experimental data to validate the simulation force field and protocols.…”

Section: Introductionmentioning

confidence: 99%

Experimental and theoretical studies of emodin interacting with a lipid bilayer of DMPC

et al. 2017

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Emodin is one of the most abundant anthraquinone derivatives found in nature. It is the active principle of some traditional herbal medicines with known biological activities. In this work, we combined experimental and theoretical studies to reveal information about location, orientation, interaction and perturbing effects of Emodin on lipid bilayers, where we have taken into account the neutral form of the Emodin (EMH) and its anionic/deprotonated form (EM − ). Using both UV/Visible spectrophotometric techniques and molecular dynamics (MD) simulations, we showed that both EMH and EM − are located in a lipid membrane. Additionally, using MD simulations, we revealed that both forms of Emodin are very close to glycerol groups of the lipid molecules, with the EMH inserted more deeply into the bilayer and more disoriented relative to the normal of the membrane when compared with the EM − , which is more exposed to interfacial water. Analysis of several structural properties of acyl chains of the lipids in a hydrated pure DMPC bilayer and in the presence of Emodin revealed that both EMH and EM − affect the lipid bilayer, resulting in a remarkable disorder of the bilayer in the vicinity of the Emodin. However, the disorder caused by EMH is weaker than that caused by EM − . Our results suggest that these disorders caused by Emodin might lead to distinct effects on lipid bilayers including its disruption which are reported in the literature.

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Liposomal drug transport: A molecular perspective from molecular dynamics simulations in lipid bilayers

Cited by 140 publications

References 101 publications

Dual-resolution molecular dynamics simulation of antimicrobials in biomembranes

Dual-resolution molecular dynamics simulation of antimicrobials in biomembranes

Permeability of Small Molecules through a Lipid Bilayer: A Multiscale Simulation Study

Experimental and theoretical studies of emodin interacting with a lipid bilayer of DMPC

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