Diffusion of 1,2-Dimethoxyethane and 1,2-Dimethoxypropane through Phosphatidycholine Bilayers: A Molecular Dynamics Study

Samanta, Susruta; Hezaveh, Samira; Milano, Giuseppe; Roccatano, Danilo

doi:10.1021/jp211564x

Cited by 27 publications

(48 citation statements)

References 60 publications

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“…(1) Small molecule conformational sampling [73][74][75][76]; (2) Protein-folding [77][78][79] and large-scale protein conformational sampling [80][81][82][83]; (3) Protein-protein/peptide-peptide interactions [84][85][86][87][88][89][90][91][92]; (4) DNA conformational changes [93] and DNA-DNA interactions [94][95][96]; (5) Binding and association free-energies [97][98][99][100][101][102][103][104][105][106][107]; (6) Adsorption on and permeation through lipid bilayers [108][109][110][111][112][113][114][115][116][117] …”

Section: Umbrella Samplingmentioning

confidence: 99%

Enhanced Sampling in Molecular Dynamics Using Metadynamics, Replica-Exchange, and Temperature-Acceleration

Abrams

Bussi

2013

Entropy

399

405

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Abstract:We review a selection of methods for performing enhanced sampling in molecular dynamics simulations. We consider methods based on collective variable biasing and on tempering, and offer both historical and contemporary perspectives. In collective-variable biasing, we first discuss methods stemming from thermodynamic integration that use mean force biasing, including the adaptive biasing force algorithm and temperature acceleration.We then turn to methods that use bias potentials, including umbrella sampling and metadynamics. We next consider parallel tempering and replica-exchange methods.We conclude with a brief presentation of some combination methods.

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Section: Umbrella Samplingmentioning

confidence: 99%

Enhanced Sampling in Molecular Dynamics Using Metadynamics, Replica-Exchange, and Temperature-Acceleration

Abrams

Bussi

2013

Entropy

399

405

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“…The partition of a drug could be either predicted by long nano-second classical MDS, or by the Potential of Mean Force (PMF) methods (37,38). Using MDS on various fluorescent azaaromatic probes on water-membrane, it has been earlier shown that the probe localization is determined by the electrostatic dipole-dipole and van der Waals interactions (39).…”

Section: Introductionmentioning

confidence: 99%

Computational and experimental evidence to the permeability of withanolides across the normal cell membrane

Wadhwa¹,

Yadav

Katiyar

et al. 2019

Preprint

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Poor bioavailability due to the inability to cross the cell membrane is one of the major reasons for the failure of a drug in the clinical trials. We have used molecular dynamics simulations to predict the membrane permeability of natural drugs -withanolides (withaferin-A and withanone) that have similar structures but remarkably differ in their cytotoxicity. We found that withaferin-A, but not withanone, could proficiently transverse through the model membrane. The free energy profiles obtained were in accordance with the physico-chemical properties of the investigated drug molecules. It was observed that the polar head group of the bilayer exhibits high resistance for the passage of withanone as compared to withaferin-A, while the interior of the membrane behaves similarly for both withanolides. The solvation analysis revealed that the high solvation of terminal O5 oxygen of withaferin-A was the major driving force. The impact of the favorable interaction of terminal oxygen (O5) of withaferin-A with the phosphate of the membrane led to its smooth passage across the bilayer. The computational predictions were validated by raising and recruiting unique antibodies that react to withaferin-A and withanone.Further, the time-lapsed analyses of control and treated human normal and cancer cells, demonstrated proficient permeation of withaferin-A, but not withanone, through normal cells.These data strongly validated our computational method for predicting permeability and hence bioavailability of candidate compounds in the drug development process. Statement of significanceWhat determines the bioavailability of a drug? Does the ability to cross cell membrane determine this? A combined simulation/experimental study of the permeability of two natural drugswithanolides (Wi-A and Wi-N) across the cell membrane was conducted. In the computational portion of the study, steered MD simulations were performed to investigate the propensity of the two molecules to permeate across the cell. It is found that Wi-A proceeds relatively simply across the cell compared to Wi-N. This trend was found to be consistent with experiment. This work is an important step towards understanding the molecular basis of permeability of natural drug molecules.

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“…Theoretical calculations offer a valuable alternative to experiments, among which molecular dynamics method can be used to investigate the interactions between drug and model membrane, estimate its preferred position and predicate its permeability. Drug partitioning could be predicted by long-time traditional molecular dynamics, [2][3][4][5] or by potential of mean force (PMF) method that calculates the free energy profile of a drug along the bilayer normal [5,6], etc. We [7] have calculated the free energy profiles of three drugs with different permeability using PMF method, and the results show that the obtained energy barrier is correlated well with drug's permeability.…”

Section: Introductionmentioning

confidence: 99%

Concentration effect of cimetidine with POPC bilayer: a molecular dynamics simulation study

Wang

Meng²

2016

Molecular Simulation

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a tianjin Key laboratory of Molecular Design and Drug Discovery, tianjin institute of Pharmaceutical research, tianjin, P.r. china; b State Key laboratory of Drug Delivery technology and Pharmacokinetics, tianjin institute of Pharmaceutical research, tianjin, P.r. china ABSTRACT All-atom molecular dynamics simulations have been performed on cimetidine in the presence of a palmitoyloleoylphosphatidylcholine (POPC) bilayer. The free energy profile of a single cimetidine molecule passing across POPC bilayer displays a minimum at the interface of bilayer and water. Ten cimetidine molecules were inserted into POPC bilayer to obtain an 8 mol % drug model, and molecular dynamics results showed that cimetidine molecules reside at the polar region of POPC bilayer with sulphur atoms directing to the hydrophobic region. By comparing the one drug model with 8 mol % drug model, one can see that the central barrier to cross the membrane increases while the free energy in bulk water decreases, indicating that the ability of cimetidine passing across the POPC bilayer weakens at increased concentration. In addition, the free energy minimum shifts closer to the hydrophobic core. Our results indicate that with the increased drug concentration, it is more difficult for cimetidine to enter and pass across POPC bilayer.

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Diffusion of 1,2-Dimethoxyethane and 1,2-Dimethoxypropane through Phosphatidycholine Bilayers: A Molecular Dynamics Study

Cited by 27 publications

References 60 publications

Enhanced Sampling in Molecular Dynamics Using Metadynamics, Replica-Exchange, and Temperature-Acceleration

Enhanced Sampling in Molecular Dynamics Using Metadynamics, Replica-Exchange, and Temperature-Acceleration

Computational and experimental evidence to the permeability of withanolides across the normal cell membrane

Concentration effect of cimetidine with POPC bilayer: a molecular dynamics simulation study

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