Abstract
Gene therapy is an important therapeutic strategy in the treatment of a wide range of genetic disorders. Delivery of genetic materials into patient cells is limited since nucleic acids are vulnerable to degradation in extra- and intra-cellular environments. Design of delivery vehicles can overcome these limitations. Polymers and lipids are effective non-viral nucleic acid carriers; they can form stable complexes with nucleic acids known as polyplexes and lipoplexes. Despite the great amount of experimental work pursued on polymer or lipid based gene delivery systems, detailed atomic level information is needed for a better understanding of the roles the polymers and lipids play during delivery. This chapter will review molecular dynamics simulations performed on polyplexes and lipoplexes at critical stages of gene delivery. Interactions between various carriers and nucleic acids during the formation of polyplexes/lipoplexes, condensation and aggregation of nucleic acids facilitated by the carriers, binding of the polyplexes/lipoplexes to cell membrane, as well as their intracellular pathway are reviewed; and the gaps in the theoretical field are highlighted.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Abbreviations
- RNAi :
-
RNA interference
- dsRNA:
-
Double stranded RNA
- RISC:
-
RNA-induced silencing complex
- siRNA :
-
Short interfering RNA
- DOPC:
-
1,2-Dioleoyl-sn-glycero-3-phosphocholine
- DOPE:
-
Dioleoylphosphatidylethanolamine
- DOTAP:
-
1,2-Dioleoyl-3-trimethylammonium-propane
- DMTAP:
-
Dimyristoyltrimethylammonium propane
- DMPC:
-
Dimyristoylphosphatidylcholine
- DPPC:
-
Dipalmitoylphosphatidylcholine
- PAMAM:
-
Polyamidoamine
- PBAE:
-
Poly(beta-amino ester)
- PEI:
-
Polyethylenimine
- PLL:
-
Poly-L-lysine
- CDP:
-
Cyclodextrin-polycation
- CME:
-
Clathrin-mediated endocytosis
- CvME:
-
Caveolae/raft-mediated endocytosis
- EGF:
-
Epidermal growth factor
- MD:
-
Molecular dynamics
- MM:
-
Molecular mechanics
- QM:
-
Quantum mechanics
- PME:
-
Particle mesh Ewald
- PBC:
-
Periodic boundary conditions
- DPD:
-
Dissipative particle dynamics
- US:
-
Umbrella sampling
- WHAM:
-
Weighted histogram analysis method
- DFT:
-
Density functional theory
- CG:
-
Coarse-graining
- PTI:
-
Pancreatic trypsin inhibitor
- ENM:
-
Elastic network model
- LJ:
-
Lennard-Jones
- MM-PBSA:
-
Molecular mechanic/Poisson–Boltzmann surface area
- DAP:
-
1,3-Diaminopropane
- DAPMA:
-
N,N-Di-(3-aminopropyl)-N-(methyl)amine
- TAP:
-
Trimethylammonium
- MC:
-
Monte Carlo
- PMF:
-
Potential of mean force
- CA:
-
Caprylic acid
- LA:
-
Linoleic acid
References
Aliabadi HM, Landry B, Sun C et al (2012) Supramolecular assemblies in functional siRNA delivery: where do we stand? Biomaterials 33:2546–2569
Andersen H (1980) Molecular dynamics simulations at constant pressure and/or temperature. J Chem Phys 72:2384
Andersen HC (1983) Rattle: a “velocity” version of the shake algorithm for molecular dynamics calculations. J Comput Phys 52:24–34
Bagai S, Sun C, Tang T (2013) Potential of mean force of polyethylenimine-mediated DNA attraction. J Phys Chem B 117:49–56
Bandyopadhyay S, Tarek M, Klein ML (1999) Molecular dynamics study of a lipid-DNA complex. J Phys Chem B 103:10075–10080
Berendsen HJC, Postma JPM, van Gunsteren WF et al (1984) Molecular dynamics with coupling to an external bath. J Chem Phys 81:3684
Bloomfield VA (1996) DNA condensation. Curr Opin Struct Biol 6:334–341
Boussif O, Lezoualc’h F, Zanta MA et al (1995) A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: polyethylenimine. Proc Natl Acad Sci USA 92:7297–7301
Braun CS, Jas GS, Choosakoonkriang S et al (2003) The structure of DNA within cationic lipid/DNA complexes. Biophys J 84:1114–1123
Brooks BR, Bruccoleri RE, Olafson BD et al (1983) Charmm—a program for macromolecular energy, minimization, and dynamics calculations. J Comput Chem 4:187–217
Buneman O (1967) Time-reversible difference procedures. J Comput Phys 1:517–535
Corsi J, Hawtin RW, Ces O et al (2010) DNA lipoplexes: formation of the inverse hexagonal phase observed by coarse-grained molecular dynamics simulation. Langmuir 26:12119–12125
Dai L, Mu Y, Nordenskiold L et al (2008) Molecular dynamics simulation of multivalent-ion mediated attraction between DNA molecules. Phys Rev Lett 100:118301
Darden T, York D, Pedersen L (1993) Particle mesh Ewald: an N·log(N) method for Ewald sums in large systems. J Chem Phys 98:10089–10092
Dias RS, Pais AACC, Miguel MG et al (2003) Modeling of DNA compaction by polycations. J Chem Phys 119:8150–8157
Ding HM, Ma YQ (2013) Design maps for cellular uptake of gene nanovectors by computer simulation. Biomaterials 34:8401–8407
Dinh AT, Pangarkar C, Theofanous T et al (2007) Understanding intracellular transport processes pertinent to synthetic gene delivery via stochastic simulations and sensitivity analyses. Biophys J 92:831–846
Dominska M, Dykxhoorn DM (2010) Breaking down the barriers: siRNA delivery and endosome escape. J Cell Sci 123(Pt 8):1183–1189
Elbashir SM, Harborth J, Lendeckel W et al (2001) Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411:494–498
Elder RM, Emrick T, Jayaraman A (2011) Understanding the effect of polylysine architecture on DNA binding using molecular dynamics simulations. Biomacromolecules 12:3870–3879
Elouahabi A, Ruysschaert JM (2005) Formation and intracellular trafficking of lipoplexes and polyplexes. Mol Ther 11:336–347
Farago O, Gronbech-Jensen N (2009) Simulation of self-assembly of cationic lipids and DNA into structured complexes. J Am Chem Soc 131:2875–2881
Farago O, Gronbech-Jensen N, Pincus P (2006) Mesoscale computer modeling of lipid-DNA complexes for gene therapy. Phys Rev Lett 96:018102
Fire A, Xu S, Montgomery MK et al (1998) Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391:806–811
Fynan EF, Webster RG, Fuller DH et al (1993) DNA vaccines: protective immunizations by parenteral, mucosal, and gene-gun inoculations. Proc Natl Acad Sci USA 90:11478–11482
González MA (2011) Force fields and molecular dynamics simulations. Collect SFN 12:169–200
Gosule LC, Schellman JA (1978) DNA condensation with polyamines I. Spectroscopic studies. J Mol Biol 121:311–326
Goula D, Remy JS, Erbacher P et al (1998) Size, diffusibility and transfection performance of linear PEI/DNA complexes in the mouse central nervous system. Gene Ther 5:712–717
Groenhof G (2013) Introduction to QM/MM simulations. In: Monticelli L, Salonen E (eds) Methods in molecular biology biomolecular simulations: methods and protocols. Springer Science Business Media, New York, pp 43–66
Guo P, Coban O, Snead NM et al (2010) Engineering RNA for targeted siRNA delivery and medical application. Adv Drug Deliv Rev 62:650–666
Hayashi Y, Ullner M, Linse P (2002) A Monte Carlo study of solutions of oppositely charged polyelectrolytes. J Chem Phys 116:6836–6845
Hayashi Y, Ullner M, Linse P (2003) Complex formation in solutions of oppositely charged polyelectrolytes at different polyion compositions and salt content. J Phys Chem B 107:8198–8207
Hayashi Y, Ullner M, Linse P (2004) Oppositely charged polyelectrolytes. Complex formation and effects of chain asymmetry. J Phys Chem B 108:15266–15277
Hillaireau H, Couvreur P (2009) Nanocarriers’ entry into the cell: relevance to drug delivery. Cell Mol Life Sci 66:2873–2896
Hockney RW (1970) The potential calculation and some applications. Meth Comput Phys 9:135–211
Hoogerbrugge PJ, Koelman JMVA (1992) Simulating microscopic hydrodynamic phenomena with dissipative particle dynamics. Europhys Lett 19:155
Hoover WG (1985) Canonical dynamics: equilibrium phase-space distributions. Phys Rev A 31(3):1695–1697
Hsu CY, Uludag H (2012) Cellular uptake pathways of lipid-modified cationic polymers in gene delivery to primary cells. Biomaterials 33:7834–7848
Ingólfsson HI, Lopez CA, Uusitalo JJ et al (2013) The power of coarse graining in biomolecular simulations. WIREs Comput Mol Sci
Jensen LB, Mortensen K, Pavan GM et al (2010) Molecular characterization of the interaction between siRNA and PAMAM G7 dendrimers by SAXS, ITC, and molecular dynamics simulations. Biomacromolecules 11:3571–3577
Jensen LB, Pavan GM, Kasimova MR et al (2011) Elucidating the molecular mechanism of PAMAM-siRNA dendriplex self-assembly: effect of dendrimer charge density. Int J Pharm 416:410–418
Jones SP, Pavan GM, Danani A et al (2010) Quantifying the effect of surface ligands on dendron-DNA interactions: insights into multivalency through a combined experimental and theoretical approach. Chemistry 16:4519–4532
Jorge AF, Dias RS, Pais AA (2012) Enhanced condensation and facilitated release of DNA using mixed cationic agents: a combined experimental and Monte Carlo study. Biomacromolecules 13:3151–3161
Journal of Gene Medicine (2013) [cited 2013 May 06]. Available from: www.wiley.co.uk/genmed/clinical
Karatasos K, Posocco P, Laurini E et al (2012) Poly(amidoamine)-based dendrimer/siRNA complexation studied by computer simulations: effects of pH and generation on dendrimer structure and siRNA binding. Macromol Biosci 12:225–240
Kircheis R, Wightman L, Wagner E (2001) Design and gene delivery activity of modified polyethylenimines. Adv Drug Deliv Rev 53:341–358
Korolev N, Lyubartsev AP, Nordenskiold L et al (2001) Spermine: an “invisible” component in the crystals of B-DNA. A grand canonical Monte Carlo and molecular dynamics simulation study. J Mol Biol 308:907–917
Korolev N, Lyubartsev AP, Laaksonen A et al (2002) On the competition between water, sodium ions, and spermine in binding to DNA: a molecular dynamics computer simulation study. Biophys J 82:2860–2875
Korolev N, Lyubartsev AP, Laaksonen A et al (2003) A molecular dynamics simulation study of oriented DNA with polyamine and sodium counterions: diffusion and averaged binding of water and cations. Nucleic Acids Res 31:5971–5981
Korolev N, Lyubartsev AP, Laaksonen A et al (2004a) Molecular dynamics simulation study of oriented polyamine- and Na-DNA: sequence specific interactions and effects on DNA structure. Biopolymers 73:542–555
Korolev N, Lyubartsev AP, Laaksonen A et al (2004b) A molecular dynamics simulation study of polyamine- and sodium-DNA. Interplay between polyamine binding and DNA structure. Eur Biophys J 33:671–682
Kumar S, Rosenberg JM, Bouzida D et al (1992) The weighted histogram analysis method for free-energy calculations on biomolecules. I. The method. J Comput Chem 13:1011–1021
Lamoureux G, Roux B (2003) Modeling induced polarization with classical Drude oscillators: theory and molecular dynamics simulation algorithm. J Chem Phys 119:3025–3039
Leach AR (2001) Molecular modeling principles and applications. Pearson Education Limited, Great Britain
Levitt M, Warshel A (1975) Computer-simulation of protein folding. Nature 253:694–698
Lindahl ER (2008) Molecular dynamic simulations. In: Kukol A (ed) Methods in molecular biology molecular modeling of proteins. Humana Press, pp 3–23
Lorenz C, Hadwiger P, John M et al (2004) Steroid and lipid conjugates of siRNAs to enhance cellular uptake and gene silencing in liver cells. Bioorg Med Chem Lett 14:4975–4977
Lyubartsev A, Tu YQ, Laaksonen A (2009) Hierarchical multiscale modelling scheme from first principles to mesoscale. J Comput Theor Nanosci 6:951–959
Maiti PK, Bagchi B (2006) Structure and dynamics of DNA-dendrimer complexation: role of counterions, water, and base pair sequence. Nano Lett 6:2478–2485
Matranga C, Tomari Y, Shin C et al (2005) Passenger-strand cleavage facilitates assembly of siRNA into Ago2-containing RNAi enzyme complexes. Cell 123:607–620
McCammon JA, Gelin BR, Karplus M (1977) Dynamics of folded proteins. Nature 267:585–590
McNeish IA, Bell SJ, Lemoine NR (2004) Gene therapy progress and prospects: cancer gene therapy using tumour suppressor genes. Gene Ther 11:497–503
Meller J (2001) Molecular dynamics. In: Encyclopedia of life sciences. Nature Publishing Group
Mills M, Orr B, Banaszak Holl MM et al (2010) Microscopic basis for the mesoscopic extensibility of dendrimer-compacted DNA. Biophys J 98:834–842
Mills M, Orr BG, Banaszak Holl MM et al (2013) Attractive hydration forces in DNA-dendrimer interactions on the nanometer scale. J Phys Chem B 117:973–981
Monard G, Merz KM (1999) Combined quantum mechanical/molecular mechanical methodologies applied to biomolecular systems. Acc Chem Res 32:904–911
Monticelli L, Tieleman DP (2013) Force fields for classical molecular dynamics. In: Monticelli L, Salonen E (eds) Methods in molecular biology biomolecular simulations: methods and protocols. Springer Science Business Media, New York, pp 197–213
Moret I, Esteban Peris J, Guillem VM et al (2001) Stability of PEI-DNA and DOTAP-DNA complexes: effect of alkaline pH, heparin and serum. J Control Release 76:169–181
Nandy B, Maiti PK (2011) DNA compaction by a dendrimer. J Phys Chem B 115:217–230
Nosé S (1984) A molecular dynamics method for simulations in the canonical ensemble. Mol Phys 52:255–268
Ouyang D, Zhang H, Herten DP et al (2010a) Structure, dynamics, and energetics of siRNA-cationic vector complexation: a molecular dynamics study. J Phys Chem B 114:9220–9230
Ouyang D, Zhang H, Parekh HS et al (2010b) Structure and dynamics of multiple cationic vectors-siRNA complexation by all-atomic molecular dynamics simulations. J Phys Chem B 114:9231–9237
Ouyang D, Zhang H, Parekh HS et al (2011) The effect of pH on PAMAM dendrimer-siRNA complexation: endosomal considerations as determined by molecular dynamics simulation. Biophys Chem 158:126–133
Pack DW, Hoffman AS, Pun S et al (2005) Design and development of polymers for gene delivery. Nat Rev Drug Discov 4:581–593
Patria RK, Beale PD (2011) Statistical mechanics. Elsevier, United States
Pavan GM, Danani A, Pricl S et al (2009) Modeling the multivalent recognition between dendritic molecules and DNA: understanding how ligand “sacrifice” and screening can enhance binding. J Am Chem Soc 131:9686–9694
Pavan GM, Albertazzi L, Danani A (2010a) Ability to adapt: different generations of PAMAM dendrimers show different behaviors in binding siRNA. J Phys Chem B 114:2667–2675
Pavan GM, Kostiainen MA, Danani A (2010b) Computational approach for understanding the interactions of UV-degradable dendrons with DNA and siRNA. J Phys Chem B 114:5686–5693
Pavan GM, Mintzer MA, Simanek EE et al (2010c) Computational insights into the interactions between DNA and siRNA with “rigid” and “flexible” triazine dendrimers. Biomacromolecules 11:721–730
Pavan GM, Posocco P, Tagliabue A et al (2010d) PAMAM dendrimers for siRNA delivery: computational and experimental insights. Chemistry 16:7781–7795
Pearlman DA, Case DA, Caldwell JW et al (1995) Amber, a package of computer-programs for applying molecular mechanics, normal-mode analysis, molecular-dynamics and free energy calculations to simulate the structural and energetic properties of molecules. Comput Phys Commun 91:1–41
Pegg AE, McCann PP (1982) Polyamine metabolism and function. Am J Physiol 243:C212–C221
Phillips JC, Braun R, Wang W et al (2005) Scalable molecular dynamics with NAMD. J Comput Chem 26:1781–1802
Posocco P, Pricl S, Jones S et al (2010) Less is more—multiscale modelling of self-assembling multivalency and its impact on DNA binding and gene delivery. Chem Sci 1:393–404
Potter H (1988) Electroporation in biology: methods, applications, and instrumentation. Anal Biochem 174:361–373
Rappe AK, Goddard IWA (1991) Charge equilibration for molecular dynamics simulations. J Phys Chem 95:3358–3363
Razin S, Rozansky R (1959) Mechanism of the antibacterial action of spermine. Arch Biochem Biophys 81:36–54
Roth JA, Nguyen D, Lawrence DD et al (1996) Retrovirus-mediated wild-type p53 gene transfer to tumors of patients with lung cancer. Nat Med 2:985–991
Ryckaert JP, Ciccotti G, Berendsen HJC (1977) Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. J Comput Phys 23:327–341
Sagui C, Darden TA (1999) Molecular dynamics simulations of biomolecules: long-range electrostatic effects. Annu Rev Biophys Biomol Struct 28:155–179
Salinas SRA (2001) Introduction to statistical physics. Springer, New York
Saunders MG, Voth GA (2013) Coarse-graining methods for computational biology. Annu Rev Biophys 42:73–93
Savelyev A, Papoian GA (2007) Inter-DNA electrostatics from explicit solvent molecular dynamics simulations. J Am Chem Soc 129:6060–6061
Schlick T (2010) Molecular modeling and simulation: an interdisciplinary guide. Springer, New York
Schneider T, Stoll E (1978) Molecular-dynamics study of a three-dimensional one-component model for distortive phase transitions. Phys Rev B 17:1302–1322
Schofield P (1973) Computer simulation studies of the liquid state. Comput Phys Commun 5:17–23
Scott WRP, Hunenberger PH, Tironi IG et al (1999) The GROMOS biomolecular simulation program package. J Phys Chem A 103:3596–3607
Senn HM, Thiel W (2007) QM/MM methods for biological systems. Atomistic approaches in modern biology: from quantum chemistry to molecular simulations 268: 173–290
Stevens MJ (2001) Simple simulations of DNA condensation. Biophys J 80:130–139
Sun C, Tang T, Uludag H (2011a) Molecular dynamics simulations of PEI mediated DNA aggregation. Biomacromolecules 12:3698–3707
Sun C, Tang T, Uludag H et al (2011b) Molecular dynamics simulations of DNA/PEI complexes: effect of PEI branching and protonation state. Biophys J 100:2754–2763
Sun C, Tang T, Uludag H (2012a) Molecular dynamics simulations for complexation of DNA with 2 kDa PEI reveal profound effect of PEI architecture on complexation. J Phys Chem B 116:2405–2413
Sun C, Tang T, Uludag H (2012b) Probing the effects of lipid substitution on polycation mediated DNA aggregation: a molecular dynamics simulations study. Biomacromolecules 13:2982–2988
Sun C, Tang T, Uludag H (2013) A molecular dynamics simulation study on the effect of lipid substitution on polyethylenimine mediated siRNA complexation. Biomaterials 34:2822–2833
Swope WC, Andersen HC, Berens PH et al (1982) A computer simulation method for the calculation of equilibrium constants for the formation of physical clusters of molecules: application to small water clusters. J Chem Phys 76:637
Szasz D (1996) Boltzmann’s ergodic hypothesis, a conjecture for centuries? Studia Scientiarum Mathematicarum Hungaria 31:299–322
Takada S (2012) Coarse-grained molecular simulations of large biomolecules. Curr Opin Struct Biol 22:130–137
Torrie GM, Valleau JP (1977) Nonphysical sampling distributions in Monte Carlo free-energy estimation: umbrella sampling. J Comput Phys 23:187–199
Tuckerman ME (2010) Statistical mechanics: theory and molecular simulation. Oxford University Press, New York
Vasumathi V, Maiti PK (2010) Complexation of siRNA with dendrimer: a molecular modeling approach. Macromolecules 43:8264–8274
Verlet L (1967) Computer “Experiments” on classical fluids. I. Thermodynamical properties of Lennard-Jones molecules. Phys Rev 159:98–103
Voth GA (2009) Coarse-graining of condensed phase and biomolecular systems. CRC Press/Taylor and Francis Group, Boca Raton
Voulgarakis NK, Rasmussen KO, Welch PM (2009) Dendrimers as synthetic gene vectors: cell membrane attachment. J Chem Phys 130:155101
Warshel A, Levitt M (1976) Theoretical studies of enzymic reactions: dielectric, electrostatic and steric stabilization of the carbonium ion in the reaction of lysozyme. J Mol Biol 103:227–249
Warshel A, Sharma P, Kato M et al (2006) Electrostatic basis for enzyme catalysis. Chem Rev 106:3210–3235
Wereszczynski J, McCammon JA (2012) Statistical mechanics and molecular dynamics in evaluating thermodynamic properties of biomolecular recognition. Q Rev Biophys 45:1–25
Yoon CS, Park JH (2010) Ultrasound-mediated gene delivery. Expert Opin Drug Deliv 7:321–330
Zhang XX, McIntosh TJ, Grinstaff MW (2012) Functional lipids and lipoplexes for improved gene delivery. Biochimie 94:42–58
Zheng M, Pavan GM, Neeb M et al (2012) Targeting the blind spot of polycationic nanocarrier-based siRNA delivery. ACS Nano 6:9447–9454
Ziebarth J, Wang Y (2009) Molecular dynamics simulations of DNA-polycation complex formation. Biophys J 97:1971–1983
Ziebarth J, Wang Y (2010) Coarse-grained molecular dynamics simulations of DNA condensation by block copolymer and formation of core-corona structures. J Phys Chem B 114:6225–6232
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer Science+Business Media Dordrecht
About this chapter
Cite this chapter
Meneksedag-Erol, D., Sun, C., Tang, T., Uludag, H. (2014). Molecular Dynamics Simulations of Polyplexes and Lipoplexes Employed in Gene Delivery. In: Prokop, A., Iwasaki, Y., Harada, A. (eds) Intracellular Delivery II. Fundamental Biomedical Technologies, vol 7. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-8896-0_15
Download citation
DOI: https://doi.org/10.1007/978-94-017-8896-0_15
Published:
Publisher Name: Springer, Dordrecht
Print ISBN: 978-94-017-8895-3
Online ISBN: 978-94-017-8896-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)