Molecular Dynamics Simulation of the Permeation of Methyldopa through POPC Phospholipid Bilayer Membrane

Fu-Yong, Bian; 云南大学化学科学与工程学院, 自然资源药物化学教育部重点实验室; Zhang, Jiwei; Wang, Dan; Xu, Shihong

doi:10.3866/pku.whxb201408271

Cited by 4 publications

(1 citation statement)

References 7 publications

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“…The theoretical basis is on the formula: Δ G = − RT ln K , where Δ G is free-energy variety, R is ideal gas constant, T is kelvin temperature, and K is the equilibrium constant of the system obtained by MD simulation. 68…”

Section: Methodsmentioning

confidence: 99%

Structural Basis and Mechanism for Vindoline Dimers Interacting with α,β-Tubulin

Zhang

Wang

et al. 2019

ACS Omega

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Vinblastine and its derivatives used in clinics as antitumor drugs often cause drug resistance and some serious side effects; thus, it is necessary to study new vinblastine analogues with strong anticancer cytotoxicity and low toxicity. We designed a dimer molecule using two vindoline-bonded dimer vindoline (DVB) and studied its interaction with α,β-tubulin through the double-sided adhesive mechanism to explore its anticancer cytotoxicity. In our work, DVB was docked into the interface between α-tubulin and β-tubulin to construct a complex protein structure, and then it was simulated for 100 ns using the molecular dynamics technology to become a stable and refined complex protein structure. Based on such a refined structure, the quantum chemistry at the level of the MP2/6-31G(d,p) method was used to calculate the binding energies for DVB interacting with respective residues. By the obtained binding energies, the active site residues for interaction with DVB were found. Up to 20 active sites of residues within α,β-tubulin interacting with DVB are labeled in β-Asp179, β-Glu207, β-Tyr210, β-Asp211, β-Phe214, β-Pro222, β-Tyr224, and β-Leu227 and α-Asn249, α-Arg308, α-Lys326, α-Asn329, α-Ala333, α-Thr334, α-Lys336, α-Lys338, α-Arg339, α-Ser340, α-Thr349, and α-Phe351. The total binding energy between DVB and α,β-tubulin is about −251.0 kJ·mol –1 . The sampling average force potential (PMF) method was further used to study the dissociation free energy (Δ G ) along the separation trajectory of α,β-tubulin under the presence of DVB based on the refined structure of DVB with α,β-tubulin. Because of the presence of DVB within the interface between α- and β-tubulin, Δ G is 252.3 kJ·mol –1 . In contrast to the absence of DVB, the separation of pure β-tubulin needs a free energy of 196.9 kJ·mol –1 . The data show that the presence of DVB adds more 55.4 kJ·mol –1 of Δ G to hinder the normal separation of α,β-tubulin. Compared to vinblastine existing, the free energy required for the separation of α,β-tubulin is 220.5 kJ·mol –1 . Vinblastine and DVB can both be considered through the same double-sided adhesive mechanism to give anticancer cytotoxicity. Because of the presence of DVB, a larger free energy is needed for the separation of α,β-tubulin, which suggests that DVB should have stronger anticancer cytotoxicity than vinblastine and shows that DVB has a broad application prospect.

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Section: Methodsmentioning

confidence: 99%

Structural Basis and Mechanism for Vindoline Dimers Interacting with α,β-Tubulin

Zhang

Wang

et al. 2019

ACS Omega

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Molecular simulation of nonfacilitated membrane permeation

Awoonor-Williams

Rowley

2016

Biochimica et Biophysica Acta (BBA) - Biomembranes

125

146

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This is a review. Non-electrolytic compounds typically cross cell membranes by passive diffusion. The rate of permeation is dependent on the chemical properties of the solute and the composition of the lipid bilayer membrane. Predicting the permeability coefficient of a solute is important in pharmaceutical chemistry and toxicology. Molecular simulation has proven to be a valuable tool for modeling permeation of solutes through a lipid bilayer. In particular, the solubility-diffusion model has allowed for the quantitative calculation of permeability coefficients. The underlying theory and computational methods used to calculate membrane permeability are reviewed. We also discuss applications of these methods to examine the permeability of solutes and the effect of membrane composition on permeability. The application of coarse grain and polarizable models is discussed. This article is part of a Special Issue entitled: Membrane Proteins edited by J.C. Gumbart and Sergei Noskov.

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Molecular dynamics simulation of d-Benzedrine transmitting through molecular channels within D₃R

Xie

Wang

et al. 2016

Journal of Biomolecular Structure and Dynamics

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Dex-Benzedrine (known as d-Benzedrine or SAT) acts in dopamine receptors of central nerve cell system. In clinic, SAT is used to treat a variety of diseases; meanwhile, it has dependence and addiction. In order to investigate the pharmacology and addiction mechanisms of SAT as a medicine, in this paper, we have studied the structure of DR complex protein with SAT, and based on which, using potential mean force with umbrella samplings and the simulated phospholipid bilayer membrane (or POPC bilayer membrane), the molecular dynamics simulation was performed to obtain free energy changes upon the trajectories for SAT moving along the molecular channels within DR. The free energy change for SAT transmitting toward the outside of cell along the functional molecular channel within DR is 83.5 kJ mol. The change of free energy for SAT to permeate into the POPC bilayer membrane along the protective molecular channel within DR is 87.7 kJ mol. Our previous work gave that the free energy for Levo-Benzedrine (RAT) transmitting toward the outside of cell along the functional molecular channel within DR is 91.4 kJ mol, while it is 117.7 kJ mol for RAT to permeate into the POPC bilayer membrane along the protective molecular channel within DR. The values of free energy suggest that SAT relatively prefers likely to pass through the functional molecular channel within DR for increasing the release of dopamine molecules resulting in a variety of functional effects for SAT. The obtained results show that the pharmacology and addiction mechanisms of SAT as a drug are closely related to the molecular dynamics and mechanism for SAT transmitting along molecular channels within DR.

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Molecular Dynamics Simulation of the Permeation of Methyldopa through POPC Phospholipid Bilayer Membrane

Cited by 4 publications

References 7 publications

Structural Basis and Mechanism for Vindoline Dimers Interacting with α,β-Tubulin

Structural Basis and Mechanism for Vindoline Dimers Interacting with α,β-Tubulin

Molecular simulation of nonfacilitated membrane permeation

Molecular dynamics simulation of d-Benzedrine transmitting through molecular channels within D₃R

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Molecular Dynamics Simulation of the Permeation of Methyldopa through POPC Phospholipid Bilayer Membrane

Cited by 4 publications

References 7 publications

Structural Basis and Mechanism for Vindoline Dimers Interacting with α,β-Tubulin

Structural Basis and Mechanism for Vindoline Dimers Interacting with α,β-Tubulin

Molecular simulation of nonfacilitated membrane permeation

Molecular dynamics simulation of d-Benzedrine transmitting through molecular channels within D3R

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Molecular dynamics simulation of d-Benzedrine transmitting through molecular channels within D₃R