Molecular Dynamics Study of Charged Dendrimers in Salt-Free Solution: Effect of Counterions

Polyamidoamine (PAMAM) dendrimers, being protonated under physiological conditions, represent a promising class of nonviral, nano-sized vectors for drug and gene delivery. We performed extensive molecular dynamics simulations of a generic model dendrimer in a salt-free solution with dendrimer's terminal beads positively charged. Solvent molecules as well as counterions were explicitly included as interacting beads. We find that the size of the charged dendrimer depends non-monotonically on the strength of electrostatic interactions demonstrating a maximum when the Bjerrum length equals the diameter of a bead. Many other structural and dynamic characteristics of charged dendrimers are also found to follow this pattern. We address such a behavior to the interplay between repulsive interactions of the charged terminal beads and their attractive interactions with oppositely charged counterions. The former favors swelling at small Bjerrum lengths and the latter promotes counterion condensation. Thus, counterions can have a dramatic effect on the structure and dynamics of charged dendrimers and, under certain conditions, cannot be treated implicitly

The Devil Is in the Details : What Do We Really Track in Single-Particle Tracking Experiments of Diffusion in Biological Membranes?

Single-particle tracking (SPT) is an experimental technique that allows one to follow the dynamics of individual molecules in biological membranes with unprecedented precision. Given the importance of lipid and membrane protein diffusion in the formation of nanoscale functional complexes, it is critical to understand what exactly is measured in SPT experiments. To clarify this issue, we employed nanoscale computer simulations designed to match SPT experiments that exploit streptavidin-functionalized Au nanoparticles (AuNPs). The results show that lipid labeling interferes critically with the diffusion process; thus, the diffusion measured in SPT is a far more complex process than what has been assumed. It turns out that the influence of AuNP-based labels on the dynamics of probe lipids includes not only the AuNP-induced viscous drag that is the more significant the larger the NP but, more importantly, also the effects related to the interactions of the streptavidin linker with membrane lipids. Due to these effects, the probe lipid moves in a concerted manner as a complex with the linker protein and numerous unlabeled lipids, which can slow down the motion of the probe by almost an order of magnitude. Furthermore, our simulations show that nonlinker streptavidin tetramers on the AuNP surface are able to interact with the membrane lipids, which could potentially lead to multivalent labeling of the NPs by the probe lipids. Our results further demonstrate that in the submicrosecond time domain the motion of the probe lipid is uncorrelated with the motion of the AuNP, showing that there is a 1 mu s limit for the temporal resolution of the SPT technique. However, this limit for the temporal resolution depends on the nanoparticle size and increases rapidly with growing AuNPs. Overall, the results provide a molecular-scale framework to accurately interpret SPT data and to design protocols that minimize label-induced artifacts.Peer reviewe

How to control interactions of cellulose-based biomaterials with skin: the role of acidity in the contact area.

Being able to control the interactions of biomaterials with living tissues and skin is highly desirable for many biomedical applications. This is particularly the case for cellulose-based materials which provide one of the most versatile platforms for tissue engineering due to their strength, biocompatibility and abundance. Achieving such control, however, requires detailed molecular-level knowledge of the dominant interaction mechanisms. Here, we employed both biased and unbiased atomic-scale molecular dynamics simulations to explore how cellulose crystals interact with model stratum corneum bilayers, ternary mixtures of ceramides, cholesterol, and free fatty acids. Our findings show that acidity in the contact area directly affects binding between cellulose and the stratum corneum bilayer: Protonation of free fatty acids in the bilayer promotes attractive cellulose-bilayer interactions. We identified two major factors that control the cellulose-skin interactions: (i) the electrostatic repulsion between a cellulose crystal and the charged (anionic due to deprotonated fatty acids) surface of a stratum corneum bilayer and (ii) the cellulose-stratum corneum hydrogen bonding. When less than half of the fatty acids in the bilayer are protonated, the first factor dominates and there is no binding to skin. At a larger degree of fatty acid protonation the cellulose-stratum corneum hydrogen bonding prevails yielding a tight binding. Remarkably, we found that ceramide molecules are the key component in hydrogen bonding with cellulose. Overall, our findings highlight the critical role of fatty acid protonation in biomaterial-stratum corneum interactions and can be used for optimizing the surface properties of cellulose-based materials aimed at biomedical applications such as wound dressings

Ion transport through chemically induced pores in protein-free phospholipid membranes

We address the possibility of being able to induce the trafficking of salt ions and other solutes across cell membranes without the use of specific protein-based transporters or pumps. On the basis of realistic atomic-scale molecular dynamics simulations, we demonstrate that transmembrane ionic leakage can be initiated by chemical means, in this instance through addition of dimethyl sulfoxide (DMSO), a solvent widely used in cell biology. Our results provide compelling evidence that the small amphiphilic solute DMSO is able to induce transient defects (water pores) in membranes and to promote a subsequent diffusive pore-mediated transport of salt ions. The findings are consistent with available experimental data and offer a molecularlevel explanation for the experimentally observed activities of DMSO solvent as an efficient penetration enhancer and a cryoprotectant, as well as an analgesic. Our findings suggest that transient pore formation by chemical means could emerge as an important general principle for therapeutics

Calculation of the electrostatic potential of lipid bilayers from molecular dynamics simulations: methodological issues

The electrostatic properties of lipid membranes are of profound importance as they are directly associated with membrane potential and, consequently, with numerous membrane-mediated biological phenomena. Here we address a number of methodological issues related to the computation of the electrostatic potential from atomic-scale molecular dynamics simulations of lipid bilayers. We discuss two slightly different forms of Poisson equation that are normally used to calculate the membrane potential: (i) a classical form when the potential and the electric field are chosen to be zero on one of the sides of a simulation box and (ii) an alternative form, when the potential is set to be the same on the opposite sides of a simulation box. Both forms differ by a position-dependent correction term, which has been shown to be proportional to the overall dipole moment of a bilayer system (for neutral systems). For symmetric bilayers we demonstrate that both approaches give essentially the same potential profiles, provided that simulations are long enough (a production run of at least 100 ns is required) and that fluctuations of the center of mass of a bilayer are properly accounted for. In contrast, for asymmetric lipid bilayers, the second approach is no longer appropriate due to a nonzero net dipole moment across a simulation box with a single asymmetric bilayer. We demonstrate that in this case the electrostatic potential can adequately be described by the classical form of Poisson equation, provided that it is employed in conjunction with tin-foil boundary conditions, which exactly balance a nonzero surface charge of a periodically replicated multibilayer system. Furthermore, we show that vacuum boundary conditions give qualitatively similar potential profiles for asymmetric lipid bilayers as compared to the conventional periodic boundaries, but accurate determination of the transmembrane potential difference is then hindered due to detachment of some water dipoles from bulk aqueous solution to vacuum.Peer reviewe

Defect-Mediated Trafficking across Cell Membranes: Insights from in Silico Modeling

noReview article. No abstract