Molecular simulations of vesicles and dendrimers

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.<br/

Coarse Grained Molecular Dynamics Simulations of the Fusion of Vesicles Incorporating Water Channels

As the dynamics of the cell membrane and the working mechanisms of proteins cannot be readily asserted at a molecular level, many different hypotheses exist that try to predict and explain these processes, for instance vesicle fusion. Therefore, we use coarse grained molecular dynamics simulations to elucidate the fusion mechanism of vesicles. The implementation of this method with hydrophilic and hydrophobic particles is known for its valid representation of bilayers. With a minimalistic approach, using only 3 atom types, 12 atoms per two-tailed phospholipids and incorporating only a bond potential and Lennard-Jones potential, phospholipid bilayers and vesicles can be simulated exhibiting authentic dynamics. We have simulated the spontaneous full fusion of both tiny (6 nm diameter) and larger (13 nm diameter) vesicles. We showed that, without applying constraints to the vesicles, the initial contact between two fusing vesicles, the stalk, is initiated by a bridging lipid tail that extends from the membrane spontaneously. Subsequently it is observed that the evolution of the stalk can proceed via two pathways, anisotropic and radial expansion, which is in accordance with literature. Contrary to the spherical vesicles of in vitro experiments, the fused vesicles remain tubular since the internal volume of these vesicles is too small compared to their membrane area. While the lipid bilayer has some permeability for water, it is not high enough to allow for the large flux required to equilibrate the vesicle content in the time accessible to our simulations. To increase the membrane permeability, we incorporate proteinaceous water channels, by applying the coarse grained technique to aquaporin. Even though incorporating water channels in the vesicles does significantly increase water permeability, the vesicles do not become spherical. Presumably the lipids have to be redistributed as well

Testing the Effects of a Virtual Reality Game for Aggressive Impulse Management (VR-GAIME): Study Protocol

Background: Prior laboratory findings indicate that training avoidance movements to angry faces may lower anger and aggression among healthy participants, especially those high in trait anger. To enrich this training and make it more suitable for clinical applications, it has been developed into a Virtual Reality Game for Aggressive Impulse Management (VR-GAIME).Methods: The proposed study will examine the effects of this training in a randomized controlled trial among forensic psychiatric outpatients with aggression regulation problems (N = 60). In addition to the aggression replacement training, participants will play either the VR-GAIME or a control game. Anger will be assessed using self-report. Aggressive impulses will be measured via self-report, a validated laboratory paradigm, and rated by clinicians.Discussion: The authors hypothesize that the combination of the VR-GAIME and regular aggression treatment will be more successful in reducing aggressive behavior. One of the strengths of the proposed study is that it is the first to examine the effects of a motivational intervention in a clinical sample characterized by problems in regulating anger and aggression. Another strength of the proposed study is that the VR-GAIME will be implemented as a multi-session intervention. Additionally, the VR-GAIME applies, for the first time, serious gaming and virtual reality on an avoidance motivation intervention. If positive results are found, the VR-GAIME may be systematically deployed in forensic psychiatric settings.Trial registration: The trial is registered with The Netherlands National Trial Register, number: NTR6986