Manolis Doxastakis

Synthesis and properties

Poly(D,L lactic acid) was prepared by bulk polymerization of D,L lactide, both under atmospheric pressure and in vacuum. The obtained polymeric products were characterized in terms of molecular weight, Mw, melting point, calorimetric response and swelling behaviour. All products were amorphous. Their molecular weights were determined by viscosimetry and ranged from 2×103 to 9×104. Similarly, the melting points ranged from 90 to 210°C. Swelling experiments, with specimens immersed in buffer solutions, showed that hydrolytic degradation started in a few days for the low Mw material, whereas for the higher molecular weight products it took much longer and probably followed a two-stage mechanism. This study suggests that the high molecular weight material could be an interesting carrier for the preparation of controlled release products, in cases where prolonged delivery is necessary.

Polymer-particle mixtures: Depletion and packing effects

The structure of polymers in the vicinity of spherical colloids is investigated by Monte Carlo simulations and integral equation theory. Polymers are represented by a simple bead-spring model; only repulsive Lennard-Jones interactions are taken into account. Using advanced trial moves that alter chain connectivity, depletion and packing effects are analyzed as a function of chain length and density, both at the bond and the chain level. Chain ends segregate to the colloidal surface and polymer bonds orient parallel to it. In the dilute regime, the polymer chain length governs the range of depletion and has a negligible influence on monomer packing in dense polymer melts. Polymers adopt an ellipsoidal shape, with the larger axis parallel to the surface of the particle, as they approach larger colloids. The dimensions are perturbed within the range of the depletion layer.

Detailed molecular dynamics simulation of the self-diffusion of n-alkane and cis-1,4 polyisoprene oligomer melts

Results are presented for the self-diffusion properties of monodisperse n-alkanes and cis-1,4 polyisoprene (PI) oligomer melts, as obtained through detailed atomistic molecular dynamics (MD) simulations. The simulations have been conducted in the NVT statistical ensemble on model systems thoroughly pre-equilibrated through an efficient Monte Carlo (MC) algorithm. Results for the self-diffusion coefficient D as a function of molecular weight M support a scaling law of the form D∼Mb, with b strongly depending on temperature T, for both the n-alkanes and the cis-1,4 PI melts. The simulation results have been fitted to an expression for D involving elements of Rouse dynamics and Cohen–Turnbull–Bueche chain-end (excess free volume) effects, proposed recently by von Meerwall et al. [J. Chem. Phys. 108, 4299 (1998)]. Using a geometric analysis involving tessellation of space in Delaunay tetrahedra developed by Greenfield and Theodorou [Macromolecules 26, 5461 (1993)], we have also calculated the excess chain-end...

Chain and local dynamics of polyisoprene as probed by experiments and computer simulations

The dynamics of designed short polyisoprene (PI) chains in the melt is investigated on a wide temperature window using dielectric relaxation spectroscopy and pulsed field gradient nuclear magnetic resonance (NMR). At high temperatures, molecular dynamics (MD) simulations performed using two different models (an explicit atom model and a united atom one) capture very well the dynamic properties documented experimentally. Structures pre-equilibrated with end-bridging Monte Carlo are used as initial configurations for MD runs at different temperatures, providing predictions for the temperature dependence of the dynamics of this bulk PI. Local dynamics is unique, independently of the probe (dielectric relaxation, dynamic light scattering, nuclear magnetic resonance, neutron scattering), although mean correlation times are significantly affected, to different extents, by librations. Chain dynamics over the molecular weight and temperature range studied can be described well by the Rouse model, as shown by both...

Potential of mean force between two nanometer-scale particles in a polymer solution

Expanded ensemble density-of-states simulations and a connectivity altering algorithm are used to investigate the effective interactions that arise between nanoparticles suspended in polymer solutions. Our calculations with systems of long polymeric chains reveal oscillations in the effective polymer-induced interactions between the particles, even at low concentrations. The range of these interactions is considerably longer than originally anticipated, and their origin is traced back to the chain-end effects and density fluctuations that were absent in previous treatments of these systems.

Lipid-Modulated Sequence-Specific Association of Glycophorin A in Membranes

Protein association in lipid membranes is a complex process with thermodynamics directed by a multitude of different factors. Amino-acid sequence is a molecular parameter that affects dimerization as shown by limited directed mutations along the transmembrane domains. Membrane-mediated interactions are also important although details of such contributions remain largely unclear. In this study, we probe directly the free energy of association of Glycophorin A by means of extensive parallel Monte Carlo simulations with recently developed methods and a model that accounts for sequence-specificity while representing lipid membranes faithfully. We find that lipid-induced interactions are significant both at short and intermediate separations. The ability of molecules to tilt in a specific hydrophobic environment extends their accessible interfaces, leading to intermittent contacts during protein recognition. The dimer with the lowest free energy is largely determined by the favorable lipid-induced attractive interactions at the closest distance. Finally, the coarse-grained model employed herein, together with the extensive sampling performed, provides estimates of the free energy of association that are in excellent agreement with existing data.

Detailed atomistic Monte Carlo simulations of a polymer melt on a solid surface and around a nanoparticle.

The molecular factors that govern interfacial interactions between a polymer melt and a solid surface remain largely unclear despite significant progress made in the last years. Simulations are increasingly employed to elucidate these features, however, equilibration and sampling with models of long macromolecules in such heterogeneous systems present significant challenges. In this study, we couple the application of preferential sampling techniques with connectivity-altering Monte Carlo algorithms to explore the configurational characteristics of a polyethylene melt in proximity to a surface and a highly curved nanoparticle. Designed algorithms allow efficient sampling at all length scales of large systems required to avoid finite-size effects. Using detailed atomistic models for the polymer and realistic structures for a silica surface and a fullerene, we find that at the extreme limit where particles are comparable to the polymer Kuhn segment length, curvature penalizes the formation of long train segments. As a result, an increased number of shorter contacts belonging to different chains are made competing with the anticipated decrease of the bound layer thickness with particle size if polymer adsorbed per unit area remained constant. For very small nanoparticles, formation of new train segments cannot compete with the overall reduction of adsorbance which is present irrespective of the enthalpic interactions; a result that demonstrates the need for an accurate description of polymer rigidity at these length scales.

Self-Association of Models of Transmembrane Domains of ErbB Receptors in a Lipid Bilayer

Association of transmembrane (TM) helices is facilitated by the close packing of small residues present along the amino-acid sequence. Extensive studies have established the role of such small residue motifs (GxxxG) in the dimerization of Glycophorin A (GpA) and helped to elucidate the association of TM domains in the epidermal growth factor family of receptors (ErbBs). Although membrane-mediated interactions are known to contribute under certain conditions to the dimerization of proteins, their effect is often considered nonspecific, and any potential dependence on protein sequence has not been thoroughly investigated. We recently reported that the association of GpA is significantly assisted by membrane-induced contributions as quantified in different lipid bilayers. Herein we extend our studies to explore the origin of these effects and quantify their magnitude using different amino-acid sequences in the same lipid environment. Using a coarse-grained model that accounts for amino-acid specificity, we perform extensive parallel Monte Carlo simulations of ErbB homodimerization in dipalmitoyl-phosphatidylcholine lipid bilayers. A detailed characterization of dimer formation and estimates of the free energy of association reveal that the TM domains show a significant affinity to self-associate in lipid bilayers, in qualitative agreement with experimental findings. The presence of GxxxG motifs enhances favorable protein-protein interactions at short separations. However, the lipid-induced attraction presents a more complex character than anticipated. Depending on the interfacial residues, lipid-entropic contributions support a decrease of separation or a parallel orientation to the membrane normal, with important implications for protein function.

Component segmental mobilities in an athermal polymer blend: Quasielastic incoherent neutron scattering versus simulation

The local dynamics of the miscible blend of cis-1,4 polyisoprene (PI) (70% by weight) with 1,2 polybutadiene (PVE) (30% by weight) is studied. Quasielastic incoherent neutron scattering (QENS) experiments have provided the dynamic structure factor for each component in the blend far above the glass transition temperature. Molecular dynamics simulations on the same system have given segmental relaxation functions in good agreement with the experiments. Both methods reveal differences in the mobilities of each component, even at high temperatures, emphasizing intramolecular factors. Remarkably, the segmental relaxation of the PVE component in the PI/PVE blend rich in PI resembles that of PI and not of the pure PVE.

Controlled release systems based on poly(lactic acid). An in vitro and in vivo study

A new biodegradable delivery system based on poly(lactic acid) has been formulated, with potential applications in sustained antibiotic release against bone infection. The in vitro release of a new quinolone (pefloxacin) from low molecular weight poly(D,L-lactic acid) Mw = 2×103 lasted for 56 d whereas the in vivo delivery lasted 33 d. In both cases, the release rate is controlled by the drug diffusion and the polymer degradation, which seems to be the predominant factor. For the release experiments, discs were prepared from poly (D,L-lactide) Mw = 2×104 with drug loadings of 2% and 10% w/w. It was concluded that pefloxacin concentration remains higher than the Minimum Inhibitory Concentration (MIC) against the major causative bacteria of bone infection. The results indicate that the two different types of poly(lactic acid) can be used effectively in an implantable antibiotic release system. ©2000 Kluwer Academic Publishers