Understanding Surface Interaction and Inclusion Complexes between Piroxicam and Native or Crosslinked ß-Cyclodextrins: The Role of Drug Concentration.

Drug concentration plays an important role in the interaction with drug carriers affecting the kinetics of release process and toxicology effects. Cyclodextrins (CDs) can solubilize hydrophobic drugs in water enhancing their bioavailability. In this theoretical study based on molecular mechanics and molecular dynamics methods, the interactions between ß-cyclodextrin and piroxicam, an important nonsteroidal anti-inflammatory drug, were investigated. At first, both host-guest complexes with native ß-CD in the 1:1 and in 2:1 stoichiometry were considered without assuming any initial a priori inclusion: the resulting inclusion complexes were in good agreement with literature NMR data. The interaction between piroxicam and a ß-CD nanosponge (NS) was then modeled at different concentrations. Two inclusion mechanisms were found. Moreover, piroxicam can interact with the external NS surface or with its crosslinkers, also forming one nanopore. At larger concentration, a nucleation process of drug aggregation induced by the first layer of adsorbed piroxicam molecules is observed. The flexibility of crosslinked ß-CDs, which may be swollen or quite compact, changing the surface area accessible to drug molecules, and the dimension of the aggregate nucleated on the NS surface are important factors possibly affecting the kinetics of release, which shall be theoretically studied in more detail at specific concentrations.

Dendrimer Dynamics: A Review of Analytical Theories and Molecular Simulation Methods.

The theoretical study of dendrimers is reviewed, considering both analytical approaches and molecular simulation methods. We discuss the effect of molecular symmetry on the degeneracy of the relaxation times, and then the calculation of observable quantities, in particular the intrinsic viscosity, and then the viscoelastic complex modulus and the dynamic structure factor, in comparison with the available experimental data. In particular, the maximum intrinsic viscosity with increasing molar mass is analyzed in some detail. The approximations and/or assumptions of the adopted methods are also described in connection with analogous results for polymer of a different topology, in particular linear and star polymers.

Hydrogen Bonding in a l-Glutamine-Based Polyamidoamino Acid and its pH-Dependent Self-Ordered Coil Conformation.

This paper reports on synthesis, acid-base properties, and self-structuring in water of a chiral polyamidoamino acid, M-l-Gln, obtained from the polyaddition of N,N'-methylenebisacrylamide with l-glutamine, with the potential of establishing hydrogen bonds through its prim-amide pendants. The M-l-Gln showed pH-responsive circular dichroism spectra, revealing ordered conformations. Structuring was nearly insensitive to ionic strength but sensitive to denaturing agents. The NMR diffusion studies were consistent with a population of unimolecular nanoparticles thus excluding aggregation. The M-l-Gln had the highest molecular weight and hydrodynamic radius among all polyamidoamino acids described. Possibly, transient hydrogen bonds between l-glutamine molecules and M-l-Gln growing chains facilitated the polyaddition reaction. Theoretical modeling showed that M-l-Gln assumed pH-dependent self-ordered coil conformations with main chain transoid arrangements reminiscent of the protein hairpin motif owing to intramolecular dipole moments and hydrogen bonds. The latter were most numerous at the isoelectric point (pH 4.5), where they mainly involved even topologically distant main chain amide N-H and side chain amide C=O brought to proximity by structuring. Hydrogen bonds at pH 4.5 were also suggested by variable temperature NMR. The 2D NOESY experiments at pH 4.5 confirmed the formation of compact structures through the analysis of the main chain/side chain hydrogen contacts, in line with MD simulations.

A Molecular Dynamics Study of a Photodynamic Sensitizer for Cancer Cells: Inclusion Complexes of γ-Cyclodextrins with C70.

Photodynamic therapy is an emerging treatment of tumor diseases. The complexes with γ-cyclodextrins (γ-CD) and fullerenes or their derivatives can be used as photosensitizers by direct injection into cancer cells. Using molecular mechanics and molecular dynamics methods, the stability and the geometry of the 2:1 complexes [(γ-CD)2/C70] are investigated analyzing the differences with the analogous C60 complexes, studied in a previous theoretical work and experimentally found to be much less efficient in cancer therapy. The inclusion complex of γ-CD and C70 has a 2:1 stoichiometry, the same as C60, but is significantly less stable and displays an unlike arrangement. In vacuo, mimicking an apolar solvent, the complex is compact, whereas in water the two γ-CDs encapsulate C70 forming a relatively stable complex by interacting through their primary rims, however exposing part of C70 to the solvent. Other higher-energy complexes with the γ-CDs facing different rims can form in water, but in all cases part of the hydrophobic C70 surface remains exposed to water. The stability and arrangement of these peculiar amphiphilic inclusion complexes having non-covalent interactions in water can be an important key for cancer therapy to enhance both the solubilization and the fullerene insertion into liposomes or cell membranes.

Self-Structuring in Water of Polyamidoamino Acids with Hydrophobic Side Chains Deriving from Natural α-Amino Acids.

This paper reports on synthesis, acid-base properties and self-structuring in water of chiral polyamidoamino acids (PAACs) obtained by polyaddition of N,N'-methylenebisacrylamide with l-alanine, l-valine and l-leucine (M-l-Ala, M-l-Val, M-l-Leu) with potential for selective interactions with biomolecules. The polymers maintained the acid-base properties of amino acids. In water, the circular dichroism spectra of PAACs revealed pH-dependent structuring in the range 3⁻11 and in the wavelength interval 200⁻280 nm. Taking as reference the values at pH 3, the differential molar ellipticities were plotted in the pH interval 3⁻11. Sigmoidal curves were obtained presenting inflection points at pH 8.1, 6.8 and 7.3 for M-l-Ala, M-l-Val and M-l-Leu, respectively, corresponding to the amine half-ionization. Theoretical modeling showed that PAACs assumed stable folded conformations. Intramolecular interactions led to transoid arrangements of the main chain reminiscent of protein hairpin motif. Oligomers with ten repeat units had simulated gyration radii consistent with the hydrodynamic radii obtained by dynamic light scattering.

Inclusion complexes of ß-cyclodextrin with tricyclic drugs: an X-ray diffraction, NMR and molecular dynamics study.

Tricyclic fused-ring cyclobenzaprine (1) and amitriptyline (2) form 1:1 inclusion complexes with ß-cyclodextrin (ß-CD) in the solid state and in water solution. Rotating frame NOE experiments (ROESY) showed the same geometry of inclusion for both 1/ß-CD and 2/ß-CD complexes, with the aromatic ring system entering the cavity from the large rim of the cyclodextrin and the alkylammonium chain protruding out of the cavity and facing the secondary OH rim. These features matched those found in the molecular dynamics (MD) simulations in solution and in the solid state from single-crystal X-ray diffraction of 1/ß-CD and 2/ß-CD complexes. The latter complex was found in a single conformation in the solid state, whilst the MD simulations in explicit water reproduced the conformational transitions observed experimentally for the free molecule.

Self-Ordering Secondary Structure of d- and l-Arginine-Derived Polyamidoamino Acids.

This paper reports on synthesis, acid-base properties and pH-dependent structuring in water of d-, l- and d,l-ARGO7, bioinspired polymers obtained by polyaddition of the corresponding arginine stereoisomers with N,N'-methylenebis(acrylamide). The circular dichroism spectra of d- and l-ARGO7 showed a peak at 228 nm and quickly and reversibly responded to pH changes, but were nearly unaffected by temperature, ionic strength, and denaturating agents. Theoretical modeling studies of L-ARGO7 showed that it assumed a folded structure. Intramolecular interactions led to transoid arrangements of the main chain reminiscent of the protein hairpin motif. Torsion angles showed a quite similar distribution at pH 6 and 14 consistent with the similarity of the CD spectra from pH 6 upward.

Aggregation behavior of amphiphilic cyclodextrins in a nonpolar solvent: evidence of large-scale structures by atomistic molecular dynamics simulations and solution studies.

Chemically modified cyclodextrins carrying both hydrophobic and hydrophilic substituents may form supramolecular aggregates or nanostructures of great interest. These systems have been usually investigated and characterized in water for their potential use as nanocarriers for drug delivery, but they can also aggregate in apolar solvents, as shown in the present paper through atomistic molecular dynamics simulations and dynamic light scattering measurements. The simulations, carried out with a large number of molecules in vacuo adopting an unbiased bottom-up approach, suggest the formation of bidimensional structures with characteristic length scales of the order of 10 nm, although some of these sizes are possibly affected by the assumed periodicity of the simulation cell, in particular at longer lengths. In any case, these nanostructures are stable at least from the kinetic viewpoint for relatively long times thanks to the large number of intermolecular interactions of dipolar and dispersive nature. The dynamic light scattering experiments indicate the presence of aggregates with a hydrodynamic radius of the order of 80 nm and a relatively modest polydispersity, even though smaller nanometer-sized aggregates cannot be fully ruled out. Taken together, these simulation and experimental results indicate that amphiphilically modified cyclodextrins do also form large-scale nanoaggregates even in apolar solvents.

Atomistic simulation of hydrophobin HFBII conformation in aqueous and fluorous media and at the water/vacuum interface.

Hydrophobins are proteins of interest for numerous applications thanks to their unique conformational and surface properties and their ability to self-assemble at interfaces. Here we report fully atomistic molecular mechanics and molecular dynamics results together with circular dichroism experimental data, aimed to study the conformational properties of the hydrophobin HFBII in a fluorinated solvent in comparison with a water solution and/or at an aqueous/vacuum interface. Both the atomistic simulations and the circular dichroism data show the remarkable structural stability of HFBII at all scales in all these environments, with no significant structural change, although a small cavity is formed in the fluorinated solvent. The combination of theoretical calculations and circular dichroism data can describe in detail the protein conformation and flexibility in different solvents and/or at an interface, and constitutes a first step towards the study of their self-assembly.

Separation of chiral nanotubes with an opposite handedness by chiral oligopeptide adsorption: A molecular dynamics study.

The separation of enantiomeric chiral nanotubes that can form non-covalent complexes with an unlike stability upon adsorption of chiral molecules is a process of potential interest in different fields and applications. Using fully atomistic molecular dynamics simulations, we report in this paper a theoretical study of the adsorption and denaturation of an oligopeptide formed by 16 chiral amino acids having a helical structure in the native state on both the inner and the outer surface of the chiral (10, 20) and (20, 10) single-walled carbon nanotubes having an opposite handedness, and of the armchair (16, 16) nanotube with a similar diameter for comparison. In the final adsorbed state, the oligopeptide loses in all cases its native helical conformation, assuming elongated geometries that maximize its contact with the surface through all the 16 amino acids. We find that the complexes formed by the two chiral nanotubes and the chosen oligopeptide have a strongly unlike stability both when adsorption takes place on the outer convex surface of the nanotube, and when it occurs on the inner concave surface. Thus, our molecular simulations indicate that separation of chiral, enantiomeric carbon nanotubes for instance by chromatographic methods can indeed be carried out using oligopeptides of a sufficient length.

Aggregation behaviour of amphiphilic cyclodextrins: the nucleation stage by atomistic molecular dynamics simulations.

Amphiphilically modified cyclodextrins may form various supramolecular aggregates. Here we report a theoretical study of the aggregation of a few amphiphilic cyclodextrins carrying hydrophobic thioalkyl groups and hydrophilic ethylene glycol moieties at opposite rims, focusing on the initial nucleation stage in an apolar solvent and in water. The study is based on atomistic molecular dynamics methods with a "bottom up" approach that can provide important information about the initial aggregates of few molecules. The focus is on the interaction pattern of amphiphilic cyclodextrin (aCD), which may interact by mutual inclusion of the substituent groups in the hydrophobic cavity of neighbouring molecules or by dispersion interactions at their lateral surface. We suggest that these aggregates can also form the nucleation stage of larger systems as well as the building blocks of micelles, vesicle, membranes, or generally nanoparticles thus opening new perspectives in the design of aggregates correlating their structures with the pharmaceutical properties.

Surface topography effects in protein adsorption on nanostructured carbon allotropes.

We report a molecular dynamics (MD) simulation study of protein adsorption on the surface of nanosized carbon allotropes, namely single-walled carbon nanotubes (SWNT) considering both the convex outer surface and the concave inner surface, together with a graphene sheet for comparison. These systems are chosen to investigate the effect of the surface curvature on protein adsorption at the same surface chemistry, given by sp(2) carbon atoms in all cases. The simulations show that proteins do favorably interact with these hydrophobic surfaces, as previously found on graphite which has the same chemical nature. However, the main finding of the present study is that the adsorption strength does depend on the surface topography: in particular, it is slightly weaker on the outer convex surfaces of SWNT and is conversely enhanced on the inner concave SWNT surface, being therefore intermediate for flat graphene. We additionally find that oligopeptides may enter the cavity of common SWNT, provided their size is small enough and the tube diameter is large enough for both entropic and energetic reasons. Therefore, we suggest that proteins can effectively be used to solubilize in water single-walled (and by analogy also multiwalled) carbon nanotubes through adsorption on the outer surface, as indeed experimentally found, and to functionalize them after insertion of oligopeptides within the cavity of nanotubes of appropriate size.

Titanium oxide modeling and design for innovative biomedical surfaces: a concise review.

The natural oxide layer on implantable alloys insulates the reactive underlying metal from the physiological environment, preventing substrate corrosion and device failure. This type of oxide film has had a major role in the minimization of functional failure and toxic response after implantation in the first generation biomaterials. Recent advances in theoretical, computational, and experimental surface engineering tools provide the foundation for the design of novel devices with improved performances in this regard based on conventional implantable metal alloys. An increasing number of technologies provide the possibility of tailoring chemico-physical and morphological parameters of the surface oxide layers. For some applications, such as dental implants, surface modifications result in substantial innovation and economic success. However, the selection of novel surfaces is in general based on experimental studies and has a limited theoretical and computational foundation. In this review, we offer a perspective analysis of the correlation between theoretical studies and chemical surface modification technologies, with a special emphasis on titanium oxide on Ti alloys. Theoretical approaches for the surface behavior at an atomistic level of description are presented, together with some adsorption studies on a rutile surface. The role of chemical and electrochemical surface modification technologies in modifying the TiO(2) structure, morphology, and chemistry to tailor in vivo biological response is then briefly reviewed. Finally, we discuss the role of surface modeling as a powerful design tool for a new generation of implantable devices in which metal oxide surface can be tuned to yield specific biological response.

Molecular modelling of protein adsorption on the surface of titanium dioxide polymorphs.

This paper reports a molecular modelling study of the adsorption of protein subdomains with unlike secondary structures on different surfaces of ceramic titanium dioxide (TiO(2)), forming a passivating film on titanium biomaterials that provides the interface between the bulk metal and the physiological environment, affecting its biocompatibility and performance. Using molecular dynamics methods, we study the effect of the nanoscale structure of the common TiO(2) polymorphs (rutile, anatase and brookite) on the adsorption of an albumin subdomain and on two connected fibronectin modules, respectively containing α-helices and ß-sheets. We find that the larger protein subdomain shows a stronger adsorption, as expected because of its size, but also that the three surfaces behave differently. In particular, brookite shows the weakest adsorption, whereas anatase leads to the strongest intrinsic adsorption, in particular for the fibronectin modules. Moreover, the simulations indicate a significant conformational change of the adsorbed protein subdomains with extensive surface nanopatterning. These results show that classical molecular dynamics methods can provide useful information about the influence of nanostructure and topology on protein physisorption at a fixed surface chemistry.

Trends in biomedical engineering: focus on Smart Bio-Materials and Drug Delivery.

The present article reviews on different research lines, namely: drug and gene delivery, surface modification/modeling, design of advanced materials (shape memory polymers and biodegradable stents), presently developed at Politecnico di Milano, Italy. For gene delivery, non-viral polycationic-branched polyethylenimine (b-PEI) polyplexes are coated with pectin, an anionic polysaccharide, to enhance the polyplex stability and decrease b-PEI cytotoxicity. Perfluorinated materials, specifically perfluoroether, and perfluoro-polyether fluids are proposed as ultrasound contrast agents and smart agents for drug delivery. Non-fouling, self-assembled PEG-based monolayers are developed on titanium surfaces with the aim of drastically reducing cariogenic bacteria adhesion on dental implants. Femtosecond laser microfabrication is used for selectively and spatially tuning the wettability of polymeric biomaterials and the effects of femtosecond laser ablation on the surface properties of polymethylmethacrylate are studied. Innovative functionally graded Alumina-Ti coatings for wear resistant articulating surfaces are deposited with PLD and characterized by means of a combined experimental and computational approach. Protein adsorption on biomaterials surfaces with an unlike wettability and surface-modification induced by pre-adsorbed proteins are studied by atomistic computer simulations. A study was performed on the fabrication of porous Shape Memory Polymeric structures and on the assessment of their potential application in minimally invasive surgical procedures. A model of magnesium (alloys) degradation, in a finite element framework analysis, and a bottom-up multiscale analysis for modeling the degradation mechanism of PLA matrices was developed, with the aim of providing valuable tools for the design of bioresorbable stents.

Modeling the adsorption behavior of linear end-functionalized poly(ethylene glycol) on an ionic substrate by a coarse-grained Monte Carlo approach.

The rheology of cement pastes can be controlled by polymeric dispersants such as branched polyelectrolytes that adsorb on the surfaces of silicate particles. In the present work, we analyze the adsorption behavior of ad hoc-prepared end-carboxylated poly(ethylene glycol), or PEG, on CaCO(3) particles as a model of cement in an early hydration stage. The experimental adsorption isotherms form the base of a theoretical study aimed at unraveling polymer conformational aspects of adsorption. The study was carried out with Monte Carlo simulations using a coarse-grained bead-and-spring model of linear end-charged polymer chains adsorbing on a flat, continuous, uniformly charged surface. The adsorption driving force was introduced by a Debye-Hückel electrostatic screened potential to describe the interaction between the negatively charged end group of PEG and the positively charged CaCO(3) surface empirically. With a suitable length-scale conversion between real PEG and the coarse-grained model, the calculated and experimental adsorption isotherms can be semiquantitatively compared. The theoretical results reproduce the fundamental aspects of polymer adsorption, in essential agreement with analytical approaches relating the isotherm shape to the polymer conformational properties. The conformational transition mushroom-brush of the adsorbed polymer is located on the isotherm and is related to the molecular shape. The solvent quality effect and the solution ionic strength are also considered, and their implications on the isotherms are discussed.

A molecular dynamics study of the inclusion complexes of C60 with some cyclodextrins.

The strongly hydrophobic C(60) fullerene is a carbon allotrope of huge interest in materials science and in pharmaceutical chemistry that can be solubilized in water either by extensive chemical functionalization or by inclusion in appropriate carriers such as the cyclodextrins with formation of host-guest complexes. Here we report a molecular dynamics study of the complexes formed in solution by C(60) with gamma- and delta-cyclodextrins. The most stable host-guest complex stoichiometry is determined to be 2:1 through simulations in vacuo and in explicit water by the stepwise addition of the cyclodextrins to C(60). No a priori assumption about the inclusion stoichiometry and geometry is made. The equilibrium fluctuations of the complexes that can affect the system stability are also investigated within the molecular dynamics runs.

Protein adsorption on a hydrophobic surface: a molecular dynamics study of lysozyme on graphite.

Adsorption of human lysozyme on hydrophobic graphite is investigated through atomistic computer simulations with molecular mechanics (MM) and molecular dynamics (MD) techniques. The chosen strategy follows a simulation protocol proposed by the authors to model the initial and the final adsorption stage on a bare surface. Adopting an implicit solvent and considering 10 starting molecular orientations so that all the main sides of the protein can face the surface, we first carry out an energy minimization to investigate the initial adsorption stage, and then long MD runs of selected arrangements to follow the surface spreading of the protein maximizing its adsorption strength. The results are discussed in terms of the kinetics of surface spreading, the interaction energy, and the molecular size, considering both the footprint and the final thickness of the adsorbed protein. The structural implications of the final adsorption geometry for surface aggregation and nanoscale structural organization are also pointed out. Further MD runs are carried out in explicit water for the native structure and the most stable adsorption state to assess the local stability of the geometry obtained in implicit solvent, and to calculate the statistical distribution of the water molecules around the whole lysozyme and its backbone.

Protein adsorption on biomaterial and nanomaterial surfaces: a molecular modeling approach to study non-covalent interactions.

Atomistic computer simulations of protein adsorption on the heterogeneous surface of biomaterials and nanomaterials are reviewed. First, we present a very brief introduction to some relevant issues concerning force fields and the computational methodologies currently used, in particular molecular dynamics simulations for studying non-covalent interactions in general. The main results are then discussed, considering the adsorption of different protein subdomains and of whole proteins on different surfaces of an unlike nature. In particular, we review our results for lysozyme and some protein subdomains with a different secondary structure on a strongly hydrophobic graphite surface and on a highly hydrophilic polymeric surface, and preliminary results of protein adsorption on single-walled carbon nanotubes, focusing on the effect of the surface topography and curvature. We also discuss the results obtained in other groups for other proteins or protein subdomains being adsorbed on ceramic materials, either purely ionic (MgO, hydroxyapatite) or covalent (SiO2, taken as a model for mica), and on self-assembled monolayers terminated with various chemical functionalities. The insights gained from these simulations are commented on critically, in particular the use of an implicit solvent or the use of explicit water and the lack of final equilibrium usually achieved in the latter case. Finally, we present some open issues for computer simulations of protein adsorption at an interface, and provide an outlook about possible future work in this area.

Surface hydration of polymeric (bio)materials: a molecular dynamics simulation study.

The surface hydration of some crystalline polymeric (bio)materials is investigated at room temperature using molecular mechanics and molecular dynamics techniques through the statistical distribution of the water molecules as a function of their distance from the surface atoms. Considering different crystalline polymers such as polyethylene, poly(vinylidene fluoride), and poly(m-phenylene isophthalamide), and in particular their different crystal faces, we can take into account unlike surface chemistries and their subnanoscale topologies. Such features are ultimately related to the intermolecular forces between the exposed groups of the specific crystal face and the water molecules, and those among the polymer chains, which also affects the thermal motion of the surface repeat units. We find that the parallel grooves and depressions that can be formed at the surface by the ordered hydrophobic chains may trap the nearest water molecules at short times, unless the (sub) nanoscale pattern is effectively blurred by the thermal motion of the surface units.