Molecular simulations of vesicles and dendrimers

Research output: ThesisPhd Thesis 1 (Research TU/e / Graduation TU/e)

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Regulated transport of molecules is critical in drug delivery systems as well as in living cells. At the molecular level, targeted transport is handled by nanoparticles. In the cell these carriers are vesicles, i.e., spherical lipid bilayers enclosing a liquid, that can fuse with other membranes to deliver their contents. For drug delivery, where drug efficacy can be increased by releasing the drug at the afflicted location, apart from vesicles also polymeric nanoparticles are used. Among these, dendrimers are unique for their well-controlled branched architecture and, with ends functionalized to form binding sites, they are ideal for host–guest chemistry.

As the transitions during vesicle fusion and the interactions of the dendrimer host with individual guest molecules occur on small temporal and spatial scales, they are experimentally infeasible to observe directly; we therefore study both systems with molecular dynamics simulations. Because the required time and length scales are too large for conventional all-atom simulations, we use a coarse-graining approach wherein roughly four heavy atoms form a single particle. This greatly reduces the number of particles and interactions while smoother potentials furthermore enable larger time steps.

To resolve various hypotheses on the molecular mechanisms of vesicle fusion, we investigate fusion with an elementary model with one particle type for the solvent and two more to build the lipid's hydrophilic head and two hydrophobic tails. We demonstrate that small vesicles fuse when they spontaneously come into contact. In fact, contact is initiated by individual lipids that freely extend their tails into the interstice between membranes. The contact is subsequently stabilized by additional lipids, completing the stalk structure. Addressing an issue raised by conflicting predictions from elastic continuum models, the stalk is revealed to be composed of only the contacting monolayers, yet hydrophobic voids are prevented by lipids that freely tilt and splay. From there, anisotropic and radial expansion of the stalk are both valid pathways to the hemifusion diaphragm intermediate. When the diaphragm finally degrades, the vesicle is fully fused. The vesicle does not become spherical in the remainder of the simulation, however, because the lipid and water distribution is inappropriate and spontaneous reformation is slow. By introducing several model transmembrane proteins that facilitate water transport and lipid flip-flop, we show that equilibration of both is essential for spherical vesicles. In planar bilayers these transmembrane proteins aggregate; the intensity of aggregation not only depends on the hydrophobic mismatch with the bilayer, but also on how well they fit together.

To increase our understanding of the poly(propylene imine) (PPI) dendrimer and its host–guest system analogue of urea–adamantyl-functionalized PPI (PPIUA) dendrimer and ureido acetic acid guests, we develop a comprehensive coarse-grained model. For this model, harmonic bond and angle potentials are derived from atomistic simulations with an iterative Boltzmann inversion scheme and the force field is based on thermodynamic data. Using this model, first dendrimers up to generation 7 are studied separately, effectively in a dilute solution. The dendrimers' size, shape, and branch distributions are in good agreement with atomistic simulations and SANS experiments. We find that the structural characteristics of these dendrimers stem from flexible chains constrained by configurational and spatial requirements; small dendrimers are alternatively rod-like and globular, large ones are more rigid and spherical. Concentrated solutions of dendrimers are difficult to assess at the molecular level experimentally. We study PPI dendrimers in dilute to melt conditions in large scale simulations. We find that with increasing concentration the dendrimer volume diminishes by expulsion of internal water, ultimately resulting in solvent filled cavities between stacked dendrimers. Challenging prior findings, a better calculation reveals that dendrimer interpenetration increases only slightly with concentration; even at high concentrations each dendrimer remains a distinct entity. Using the simulation data, we also demonstrate that structure factors computed analogously to experimental calculations already start to diverge at low concentrations from directly derived structure factors. PPIUA dendrimers combined with ureido acetic acid guests form dynamic patchy nanoparticles. Our simulations show that the architecture of the self-assembled macromolecular nanostructures is indeed dictated by the guest concentration. As multivalency is an effective approach to establish strong collective interactions, we systematically study guest concentration-dependent multivalent binding using mono-, bi-, and tetravalent guests. At low guest concentrations, multivalency clearly increases binding as tethered headgroups bind more often than free guests' headgroups. We find that despite an abundance of binding sites and regardless the spacer length, most of the tethered headgroups bind in close proximity. At high guest concentrations, the dendrimer becomes saturated with bound headgroups, independent of guest valency. However, in direct competition the tetravalent guests prevail over the monovalent ones. These findings demonstrate the advantage of multivalency at high as well as low concentrations.

Overall, this dissertation illustrates that molecular simulations, by providing a clear molecular picture acknowledging the disorderly nature of molecules, greatly benefit the study of nanoparticle systems at the nanoscale.
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • Department of Biomedical Engineering
  • Hilbers, Peter A.J. , Promotor
  • Markvoort, A.J. (Bart), Copromotor
Place of PublicationEindhoven
Print ISBNs978-90-386-5011-1
Publication statusAccepted/In press - 31 Dec 2020

Bibliographical note

Proefschrift. Due to Corona virus : defense postponed until further notice.

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