Andrey A. Gurtovenko

Defect-mediated trafficking across cell membranes:insights from in silico modeling

Institute of Macromolecular Compounds, Russian Academy of Sciences, Bolshoi Prospect 31, V.O., St. Petersburg, 199004 Russia, Computational Laboratory, Institute of Pharmaceutical Innovation, University of Bradford, Bradford, West Yorkshire BD7 1DP, U.K., Department of Physics, Tampere University of Technology, P.O. Box 692, FI-33101 Tampere, Finland, Aalto University, School of Science and Technology, Finland, and MEMPHYSsCenter for Biomembrane Physics, University of Southern Denmark, Odense, Denmark

Cationic DMPC/DMTAP Lipid Bilayers: Molecular Dynamics Study

Cationic lipid membranes are known to form compact complexes with DNA and to be effective as gene delivery agents both in vitro and in vivo. Here we employ molecular dynamics simulations for a detailed atomistic study of lipid bilayers consisting of a mixture of cationic dimyristoyltrimethylammonium propane (DMTAP) and zwitterionic dimyristoylphosphatidylcholine (DMPC). Our main objective is to examine how the composition of the DMPC/DMTAP bilayers affects their structural and electrostatic properties in the liquid-crystalline phase. By varying the mole fraction of DMTAP, we have found that the area per lipid has a pronounced nonmonotonic dependence on the DMTAP concentration, with a minimum around the point of equimolar DMPC/DMTAP mixture. We show that this behavior has an electrostatic origin and is driven by the interplay between positively charged TAP headgroups and the zwitterionic phosphatidylcholine (PC) heads. This interplay leads to considerable reorientation of PC headgroups for an increasing DMTAP concentration, and gives rise to major changes in the electrostatic properties of the lipid bilayer, including a significant increase of total dipole potential across the bilayer and prominent changes in the ordering of water in the vicinity of the membrane. Moreover, chloride counterions are bound mostly to PC nitrogens implying stronger screening of PC heads by Cl ions compared to TAP headgroups. The implications of these findings are briefly discussed.

Role of phosphatidylglycerols in the stability of bacterial membranes

An extensive 100-ns molecular dynamics simulation of lipid bilayer composed of mixture of phosphatidylethanolamine (PE) and phosphatidylglycerol (PG) was performed to elucidate the role of PGs to the stability of bacterial membranes. In addition, a control simulation of pure PE over 150 ns was performed. We observed that PGs decrease both the PE headgroup protrusions into the water phase, and the PE headgroup motion along bilayer normal. The above effects are caused by stronger inter-lipid interactions in the mixed bilayer: the number of hydrogen bonds created by PEs is 34% higher in the mixed than in the pure bilayer. Another contribution is due to the numerous ion-mediated inter-lipid links, which strongly enhance interface stability. That provides a plausible mechanism for preventing lipid desorption from the membrane, for example, under the influence of an organic solvent. A more compact and less dynamic interface structure also decreases membrane permeability. That provides a possible mechanism for stabilizing, e.g., bacterial membranes.

Molecular dynamics study of charged dendrimers in salt-free solution: Effect of counterions

Polyamidoamine dendrimers, being protonated under physiological conditions, represent a promising class of nonviral, nanosized vectors for drug and gene delivery. We performed extensive molecular dynamics simulations of a generic model dendrimer in a salt-free solution with dendrimers 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 nonmonotonically 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.

Dynamics of dendrimer-based polymer networks

We present a theoretical study of polymer networks, formed by connecting dendritic building blocks (DBB’s). We concentrate on the Rouse dynamics of such networks and perform our study in two steps, considering first single generalized dendrimers (GD’s) and then networks formed by such DBB’s. In GD’s the functionality f of the inner branching points may differ from the functionality fc of the core. The GD’s cover wide classes of macromolecules, such as the “classical” dendrimers (fc=f ), the dendritic wedges (fc=f−1), and the macromolecular stars (fc>2, f=2). Here we present a systematic, analytic way which allows us to treat the dynamics of individual GD’s. Then, using a general approach based on regular lattices formed by identical cells (meshes) we study the dynamics of GD-based polymer networks. Using analytical and numerical methods we determine the storage and loss moduli, G′(ω) and G″(ω). In this way we find that the intradendrimer relaxation domain of G′(ω) becomes narrower when Mcr, the number of ...

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.

Dynamics of inhomogeneous cross-linked polymers consisting of domains of different sizes

The theoretical approach is developed to describe the dynamics of inhomogeneous cross-linked polymers consisting of cross-link agglomerations. An inhomogeneous polymer is treated as an ensemble of noninteracting cross-linked regions (domains) of different sizes. We model an internal architecture of the domains in a rather regular way and assume a power law decay of the relaxation modulus inside the domains, a decay usual for a broad class of cross-linked materials on microscopic scales. Assuming a broad size distribution of the domains in cross-linked polymers due to a random character of cross linking, we demonstrate a stretched exponential time behavior of the relaxation modulus on scales larger than the average size of inhomogeneities in the polymer. We apply this general approach to some special cases of cross-linked polymers, namely to polydisperse polymer networks, to inhomogeneous meshlike networks, and to inhomogeneously cross-linked polymeric gels.

Molecular-dynamics simulation of polyimide matrix pre-crystallization near the surface of a single-walled carbon nanotube

Polyimide-based composite materials with a single-walled carbon nanotube as filler were studied by means of extensive fully-atomistic molecular-dynamics simulations. Polyimides (PI) were considered based on 1,3-bis-(3′,4-dicarboxyphenoxy)-benzene (dianhydride R) and various types of diamines: 4,4′-bis-(4′′-aminophenoxy)-diphenylsulfone (diamine BAPS) and 4,4′-bis-(4′′-aminophenoxy)-diphenyl (diamine BAPB). The influence of the chemical structure of the polyimides on the microstructure of the composite matrix near the filler surface and away from it was investigated. The formation of subsurface layers close to the nanotube surface was found for all composites considered. In the case of R–BAPB-based composites, the formation of an organized structure was shown that could be the initial stage of the matrix crystallization process observed experimentally. Similar structural features were not observed in the R–BAPS composites. Carbon nanotubes induce the elongation of R–BAPB chains in composites whereas R–BAPS chains become more compact similar to what is observed for EXTEM™ polyimide. It was shown that electrostatic interactions do not influence the microstructure of composites but slow down significantly the dynamics of PI chains in composites.

Ion dynamics in cationic lipid bilayer systems in saline solutions.

Positively charged lipid bilayer systems are a promising class of nonviral vectors for safe and efficient gene and drug delivery. Detailed understanding of these systems is therefore not only of fundamental but also of practical biomedical interest. Here, we study bilayers comprising a binary mixture of cationic dimyristoyltrimethylammoniumpropane (DMTAP) and zwitterionic (neutral) dimyristoylphosphatidylcholine (DMPC) lipids. Using atomistic molecular dynamics simulations, we address the effects of bilayer composition (cationic to zwitterionic lipid fraction) and of NaCl electrolyte concentration on the dynamical properties of these cationic lipid bilayer systems. We find that, despite the fact that DMPCs form complexes via Na(+) ions that bind to the lipid carbonyl oxygens, NaCl concentration has a rather minute effect on lipid diffusion. We also find the dynamics of Cl(-) and Na(+) ions at the water-membrane interface to differ qualitatively. Cl(-) ions have well-defined characteristic residence times of nanosecond scale. In contrast, the binding of Na(+) ions to the carbonyl region appears to lack a characteristic time scale, as the residence time distributions displayed power-law features. As to lateral dynamics, the diffusion of Na(+) ions within the water-membrane interface consists of two qualitatively different modes of motion: very slow diffusion when ions are bound to DMPC, punctuated by fast rapid jumps when detached from the lipids. Overall, the prolonged dynamics of the Na(+) ions are concluded to be interesting for the physics of the whole membrane, especially considering its interaction dynamics with charged macromolecular surfaces.

Chemically induced phospholipid translocation across biological membranes.

Chemical means of manipulating the distribution of lipids across biological membranes is of considerable interest for many biomedical applications as a characteristic lipid distribution is vital for numerous cellular functions. Here we employ atomic-scale molecular simulations to shed light on the ability of certain amphiphilic compounds to promote lipid translocation (flip-flops) across membranes. We show that chemically induced lipid flip-flops are most likely pore-mediated: the actual flip-flop event is a very fast process (time scales of tens of nanoseconds) once a transient water defect has been induced by the amphiphilic chemical (dimethylsulfoxide in this instance). Our findings are consistent with available experimental observations and further emphasize the importance of transient membrane defects for chemical control of lipid distribution across cell membranes.