Skip to main content
SpringerLink
Log in

Effect of drug amlodipine on the charged lipid bilayer cell membranes DMPS and DMPS + DMPC: a molecular dynamics simulation study

  • Original Article
  • Published:
European Biophysics Journal Aims and scope Submit manuscript

Abstract

In this work, the effects of the anti-hypertensive drug amlodipine in native and PEGylated forms on the malfunctioning of negatively charged lipid bilayer cell membranes constructed from DMPS or DMPS + DMPC were studied by molecular dynamics simulation. The obtained results indicate that amlodipine alone aggregates and as a result its diffusion into the membrane is retarded. In addition, due to their large size aggregates of the drug can damage the cell, rupturing the cell membrane. It is shown that PEGylation of amlodipine prevents this aggregation and facilitates its diffusion into the lipid membrane. The interaction of the drug with negatively charged membranes in the presence of an aqueous solution of NaCl, as the medium, is investigated and its effects on the membrane are considered by evaluating the structural properties of the membrane such as area per lipid, thickness, lipid chain order and electrostatic potential difference between bulk solution and lipid bilayer surface. The effect of these parameters on the diffusion of the drug into the cell is critically examined and discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Alsop RJ et al (2016) The lipid bilayer provides a site for cortisone crystallization at high cortisone concentrations. Sci Rep 6:22425

    Article  CAS  Google Scholar 

  • Amjad-Iranagh S et al (2013) Effects of protein binding on a lipid bilayer containing local anesthetic articaine, and the potential of mean force calculation: a molecular dynamics simulation approach. J Mol Model 19:3831–3842

    Article  CAS  Google Scholar 

  • Bunker A (2012) Poly (ethylene glycol) in drug delivery, why does it work, and can we do better? All atom molecular dynamics simulation provides some answers. Phys Proc 34:24–33

    Article  Google Scholar 

  • Caron G et al (2004) Ionization, lipophilicity, and molecular modeling to investigate permeability and other biological properties of amlodipine. Bioorg Med Chem 12:6107–6118

    Article  CAS  Google Scholar 

  • Carrillo J-MY, Dobrynin AV (2011) Layer-by-layer assembly of charged nanoparticles on porous substrates: molecular dynamics simulations. ACS Nano 5:3010–3019

    Article  CAS  Google Scholar 

  • Carrozzino JM, Khaledi MG (2004) Interaction of basic drugs with lipid bilayers using liposome electrokinetic chromatography. Pharm Res 21:2327–2335

    Article  CAS  Google Scholar 

  • Lopez Cascales J, de la Torre JG (1997) Effect of lithium and sodium ions on a charged membrane of dipalmitoylphosphatidylserine: a study by molecular dynamics simulation. Biochim Biophys Acta (BBA) Biomembr 1330:145–156

    Article  CAS  Google Scholar 

  • Chen X-J, Liang Q (2017) Combined effects of headgroup charge and tail unsaturation of lipids on lateral organization and diffusion of lipids in model biomembranes. Chin Phys B 26:048701

    Article  Google Scholar 

  • Cherstvy A (2007) Electrostatics of DNA complexes with cationic lipid membranes. J Phys Chem B 111:7914–7927

    Article  CAS  Google Scholar 

  • Cordomi A, Edholm O, Perez JJ (2008) Effect of ions on a dipalmitoyl phosphatidylcholine bilayer. A molecular dynamics simulation study. J Phys Chem B 112:1397–1408

    Article  CAS  Google Scholar 

  • Das A, Adhikari C, Chakraborty A (2017) Interaction of different divalent metal ions with lipid bilayer: impact on the encapsulation of doxorubicin by lipid bilayer and lipoplex mediated deintercalation. J Phys Chem B 121:1854–1865

    Article  CAS  Google Scholar 

  • Davis CH, Berkowitz ML (2009) Structure of the Amyloid-β (1–42) monomer absorbed to model phospholipid bilayers: a molecular dynamics study. J Phys Chem B 113:14480–14486

    Article  CAS  Google Scholar 

  • Ergun S et al (2014) Agomelatine strongly interacts with zwitterionic DPPC and charged DPPG membranes. Biochim Biophys Acta (BBA) Biomembr 1838:2798–2806

    Article  CAS  Google Scholar 

  • García Daza FA, Mackie AD (2017) Coarse-grained simulations of modified Jeffamine ED900 micelles. Molecular Simulation 44:1–8

    Google Scholar 

  • Gotrane DM et al (2010) A novel method for resolution of amlodipine. Org Process Res Dev 14:640–643

    Article  CAS  Google Scholar 

  • Gurtovenko AA, Vattulainen I (2008) Effect of NaCl and KCl on phosphatidylcholine and phosphatidylethanolamine lipid membranes: insight from atomic-scale simulations for understanding salt-induced effects in the plasma membrane. J Phys Chem B 112:1953–1962

    Article  CAS  Google Scholar 

  • Gurtovenko AA et al (2005) Effect of monovalent salt on cationic lipid membranes as revealed by molecular dynamics simulations. J Phys Chem B 109:21126–21134

    Article  CAS  Google Scholar 

  • Hess B et al (1997) LINCS: a linear constraint solver for molecular simulations. J Comput Chem 18:1463–1472

    Article  CAS  Google Scholar 

  • Hess B et al (2008) GROMACS 4: algorithms for highly efficient, load-balanced, and scalable molecular simulation. J Chem Theory Comput 4:435–447

    Article  CAS  Google Scholar 

  • Hoda N et al (2016) Curcumin specifically binds to the human calcium–calmodulin-dependent protein kinase IV: fluorescence and molecular dynamics simulation studies. J Biomol Struct Dyn 34:572–584

    Article  CAS  Google Scholar 

  • Hyvonen M (2003) Molecular dynamics simulations on phospholipid membranes, PhD Thesis, Oulun Yliopisto Institute, University of Oulu, Finland

  • Ionov M et al (2011) Interaction of cationic phosphorus dendrimers (CPD) with charged and neutral lipid membranes. Coll Surf B 82:8–12

    Article  CAS  Google Scholar 

  • Jalili S, Saeedi M (2017) Study of procaine and tetracaine in the lipid bilayer using molecular dynamics simulation. Eur Biophys J 46:265–282

    Article  CAS  Google Scholar 

  • Jalili S et al (2015) Free energy simulations of amylin I26P mutation in a lipid bilayer. Eur Biophys J 44:37–47

    Article  CAS  Google Scholar 

  • Jean-François F et al (2008) Aggregation of cateslytin β-sheets on negatively charged lipids promotes rigid membrane domains. A new mode of action for antimicrobial peptides? Biochemistry 47:6394–6402

    Article  Google Scholar 

  • Jørgensen AM et al (2007) Molecular dynamics simulations of Na+/Cl−-dependent neurotransmitter transporters in a membrane-aqueous system. ChemMedChem 2:827–840

    Article  Google Scholar 

  • Komura S, Shirotori H, Kato T (2003) Phase behavior of charged lipid bilayer membranes with added electrolyte. J Chem Phys 119:1157–1164

    Article  CAS  Google Scholar 

  • Lee BL, Kuczera K (2017) Simulating the free energy of passive membrane permeation for small molecules. Mol Simul. https://doi.org/10.1080/08927022.2017.1407029

    Article  Google Scholar 

  • Liu H et al (2016) Probing the structure and dynamics of caveolin-1 in a caveolae-mimicking asymmetric lipid bilayer model. Eur Biophys J 45:511–521

    Article  CAS  Google Scholar 

  • Lolicato F et al (2015) Resveratrol interferes with the aggregation of membrane-bound human-IAPP: a molecular dynamics study. Eur J Med Chem 92:876–881

    Article  CAS  Google Scholar 

  • Lopez Cascales J et al (1996) Molecular dynamics simulation of a charged biological membrane. J Chem Phys 104:2713–2720

    Article  CAS  Google Scholar 

  • Marrink SJ, De Vries AH, Tieleman DP (2009) Lipids on the move: simulations of membrane pores, domains, stalks and curves. Biochim Biophys Acta (BBA) Biomembr 1788:149–168

    Article  CAS  Google Scholar 

  • Metzler R, Jeon J-H, Cherstvy A (2016) Non-Brownian diffusion in lipid membranes: experiments and simulations. Biochim Biophys Acta (BBA) Biomembr 1858:2451–2467

    Article  CAS  Google Scholar 

  • Miettinen MS et al (2009) Ion dynamics in cationic lipid bilayer systems in saline solutions. J Phys Chem B 113:9226–9234

    Article  CAS  Google Scholar 

  • Mori T et al (2016) Molecular dynamics simulations of biological membranes and membrane proteins using enhanced conformational sampling algorithms. Biochim Biophys Acta (BBA) Biomembr 1858:1635–1651

    Article  CAS  Google Scholar 

  • Mukhopadhyay P, Monticelli L, Tieleman DP (2004) Molecular dynamics simulation of a palmitoyl-oleoyl phosphatidylserine bilayer with Na+ counterions and NaCl. Biophys J 86:1601–1609

    Article  CAS  Google Scholar 

  • Nademi Y et al (2014) Molecular dynamics simulations and free energy profile of paracetamol in DPPC and DMPC lipid bilayers. J Chem Sci 126:637–647

    Article  CAS  Google Scholar 

  • Ortega-Guerrero A, Espinosa-Duran JM, Velasco-Medina J (2016) TRPV1 channel as a target for cancer therapy using CNT-based drug delivery systems. Eur Biophys J 45:423–433

    Article  CAS  Google Scholar 

  • Paloncýová MT, Berka K, Otyepka M (2013) Molecular insight into affinities of drugs and their metabolites to lipid bilayers. J Phys Chem B 117:2403–2410

    Article  Google Scholar 

  • Pandit SA, Berkowitz ML (2002) Molecular dynamics simulation of dipalmitoylphosphatidylserine bilayer with Na+ counterions. Biophys J 82:1818–1827

    Article  CAS  Google Scholar 

  • Pant P, Afshan Shaikh S, Jayaram B (2017) Design and characterization of symmetric nucleic acids via molecular dynamics simulations. Biopolymers. https://doi.org/10.1002/bip.23002

    Article  PubMed  Google Scholar 

  • Patra MC et al (2014) Molecular dynamics simulation of human serum paraoxonase 1 in DPPC bilayer reveals a critical role of transmembrane helix H1 for HDL association. Eur Biophys J 43:35–51

    Article  CAS  Google Scholar 

  • Petrache HI et al (2004) Structure and fluctuations of charged phosphatidylserine bilayers in the absence of salt. Biophys J 86:1574–1586

    Article  CAS  Google Scholar 

  • Pliquett U et al (2007) High electrical field effects on cell membranes. Bioelectrochemistry 70:275–282

    Article  CAS  Google Scholar 

  • Pohar A, Likozar B (2014) Dissolution, nucleation, crystal growth, crystal aggregation, and particle breakage of amlodipine salts: modeling crystallization kinetics and thermodynamic equilibrium, scale-up, and optimization. Ind Eng Chem Res 53:10762–10774

    Article  CAS  Google Scholar 

  • Polyansky AA et al (2005) Role of lipid charge in organization of water/lipid bilayer interface: insights via computer simulations. J Phys Chem B 109:15052–15059

    Article  CAS  Google Scholar 

  • Ramirez P et al (2006) Theoretical description of the ion transport across nanopores with titratable fixed charges. Cell Biochem Biophys 44:287–312

    Article  CAS  Google Scholar 

  • Riedl S, Zweytick D, Lohner K (2011) Membrane-active host defense peptides–challenges and perspectives for the development of novel anticancer drugs. Chem Phys Lipid 164:766–781

    Article  CAS  Google Scholar 

  • Riedl S et al (2015) Human lactoferricin derived di-peptides deploying loop structures induce apoptosis specifically in cancer cells through targeting membranous phosphatidylserine. Biochim Biophys Acta (BBA) Biomembr 1848:2918–2931

    Article  CAS  Google Scholar 

  • Romo TD et al (2011) Membrane binding of an acyl-lactoferricin B antimicrobial peptide from solid-state NMR experiments and molecular dynamics simulations. Biochim Biophys Acta (BBA) Biomembr 1808:2019–2030

    Article  CAS  Google Scholar 

  • Saiz L, Bandyopadhyay S, Klein ML (2002) Towards an understanding of complex biological membranes from atomistic molecular dynamics simulations. Biosci Rep 22:151–173

    Article  CAS  Google Scholar 

  • Scrima M et al (2014) Structural features of the C8 antiviral peptide in a membrane-mimicking environment. Biochim Biophys Acta (BBA) Biomembr 1838:1010–1018

    Article  CAS  Google Scholar 

  • Shimokawa N et al (2010) Phase separation of a mixture of charged and neutral lipids on a giant vesicle induced by small cations. Chem Phys Lett 496:59–63

    Article  CAS  Google Scholar 

  • Siontorou CG et al (2017) Artificial lipid membranes: past, present, and future. Membranes 7:38

    Article  Google Scholar 

  • Slochower DR et al (2014) Counterion-mediated pattern formation in membranes containing anionic lipids. Adv Coll Interface Sci 208:177–188

    Article  CAS  Google Scholar 

  • Sun Y et al (2008) The bound states of amphipathic drugs in lipid bilayers: study of curcumin. Biophys J 95:2318–2324

    Article  CAS  Google Scholar 

  • Sun L et al (2018) Coarse-grained molecular dynamics simulation of interactions between cyclic lipopeptide Bacillomycin D and cell membranes. Mol Simul 44:364–376

    Article  CAS  Google Scholar 

  • Van Der Spoel D et al (2005) GROMACS: fast, flexible, and free. J Comput Chem 26:1701–1718

    Article  Google Scholar 

  • Verma A, Stellacci F (2010) Effect of surface properties on nanoparticle–cell interactions. Small 6:12–21

    Article  CAS  Google Scholar 

  • Wagner AJ, May S (2007) Electrostatic interactions across a charged lipid bilayer. Eur Biophys J 36:293–303

    Article  CAS  Google Scholar 

  • Wang H, Meng F (2016) Concentration effect of cimetidine with POPC bilayer: a molecular dynamics simulation study. Mol Simul 42:1292–1297

    Article  CAS  Google Scholar 

  • Wu J, Morikis D (2006) Molecular thermodynamics for charged biomacromolecules. Fluid Phase Equilib 241:317–333

    Article  CAS  Google Scholar 

  • Yang L, Tucker IG, Østergaard J (2011) Effects of bile salts on propranolol distribution into liposomes studied by capillary electrophoresis. J Pharm Biomed Anal 56:553–559

    Article  CAS  Google Scholar 

  • Yousefpour A et al (2013) Molecular dynamics simulation of nonsteroidal antiinflammatory drugs, naproxen and relafen, in a lipid bilayer membrane. Int J Quantum Chem 113:1919–1930

    Article  CAS  Google Scholar 

  • Yousefpour A et al (2015) Interaction of PEGylated anti-hypertensive drugs, amlodipine, atenolol and lisinopril with lipid bilayer membrane: a molecular dynamics simulation study. Biochim Biophys Acta (BBA) Biomembr 1848:1687–1698

    Article  CAS  Google Scholar 

  • Yousefpour A et al (2017) Combination of anti-hypertensive drugs: a molecular dynamics simulation study. J Mol Model 23:158

    Article  Google Scholar 

  • Zhang Y et al (2010) Targeting therapy with mitosomal daunorubicin plus amlodipine has the potential to circumvent intrinsic resistant breast cancer. Mol Pharm 8:162–175

    Article  Google Scholar 

  • Zhang T et al (2018) Characterizing the interactions of two lipid modifications with lipid rafts: farnesyl anchors vs. palmitoyl anchors. Eur Biophys J 47:19–30

    Article  CAS  Google Scholar 

  • Zhou F, Schulten K (1995) Molecular dynamics study of a membrane–water interface. J Phys Chem 99:2194–2207

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Chemical Engineering, Amirkabir University of Technology (Tehran Polytechnic), 424 Hafez Ave, Tehran, P.O. Box 15875-4413, Iran

    Abbas Yousefpour, Sepideh Amjad-Iranagh & Hamid Modarress

  2. Department of Polymer Engineering, Amirkabir University of Technology (Tehran Polytechnic), Tehran, Iran

    Fatemeh Goharpey

Authors
  1. Abbas Yousefpour
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sepideh Amjad-Iranagh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fatemeh Goharpey
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hamid Modarress
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hamid Modarress.

Ethics declarations

Conflict of interest

The authors declare no conflicts of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

FigSM. 1

Drug-drug intermolecular distance for the simulation systems. (TIFF 1693 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yousefpour, A., Amjad-Iranagh, S., Goharpey, F. et al. Effect of drug amlodipine on the charged lipid bilayer cell membranes DMPS and DMPS + DMPC: a molecular dynamics simulation study. Eur Biophys J 47, 939–950 (2018). https://doi.org/10.1007/s00249-018-1317-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00249-018-1317-z

Keywords

Search

Navigation