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We investigate the previously postulated hydrodynamic steering phenomenon, resulting from complication of molecular shapes, its magnitude and possible relevance for protein--ligand and protein--protein diffusional encounters, and the kinetics of diffusion-controlled association. We consider effects of hydrodynamic interactions in a prototypical model system consisting of a cleft enzyme and an elongated substrate, and real protein--protein complexes, that of barnase and barstar, and human growth hormone and its binding protein. The kinetics of diffusional encounters is evaluated on the basis of rigid-body Brownian dynamics simulations in which hydrodynamic interactions between molecules are modeled using the bead-shell method for detailed description of molecular surfaces, and the first-passage-time approach. We show that magnitudes of steering torques resulting from the hydrodynamic coupling of associating molecules, evaluated for the studied systems on the basis of the Stokes--Einstein type relations for arbitrarily shaped rigid bodies, are comparable with magnitudes of torques resulting from electrostatic interactions of binding partners. Surprisingly, however, unlike in the case of electrostatic torques that strongly affect the diffusional encounter, overall effects of hydrodynamic steering torques on the association kinetics, while clearly discernible in Brownian dynamics simulations, are rather minute. We explain this result as a consequence of the thermal agitation of the binding partners. Our finding is relevant for the general understanding of a wide spectrum of molecular processes in solution but there is also a more practical aspect to it if one considers the low level of shape detail of models that are usually employed to evaluate hydrodynamic interactions in particle-based Stokesian and Brownian dynamics simulations of multicomponent biomolecular systems. Results described in the current work justify, in part at least, such a low-resolution description. [ABSTRACT FROM AUTHOR]

In this paper, X-ray diffraction (XRD), differential scanning calorimetry (DSC), broadband dielectric (BDS), and Fourier transform infrared (FTIR) spectroscopy supported by molecular dynamics (MD) simulations and quantum chemical computations were applied to investigate the structural and thermal properties, molecular dynamics, and H-bonding pattern of R -, S -, and RS -flurbiprofen (FLP). Experimental data indicated various spatial molecular arrangements in crystalline forms of examined systems, which seemed to disappear in the liquid state. Surprisingly, deeper analysis of high-pressure dielectric data revealed unexpected variation in the activation volume of pure enantiomers and a racemate. MD simulations showed that it is an effect of the clusterization phenomenon and a higher population of small associates in the former samples. Moreover, theoretical consideration exposed the particular role of unspecific F-Π interactions as a driving force underlying local molecular arrangements of molecules in the liquid and the crystal lattice of R -, S -, and RS -FLP.

Novel multifunctional biomimetic injectable hybrid systems were synthesized. The physicochemical as well as biological in vitro and in vivo tests demonstrated that they are promising candidates for bone tissue regeneration. The hybrids are composed of a biopolymeric collagen/chitosan/hyaluronic acid matrix and amine group-functionalized silica particles decorated with apatite to which the alendronate molecules were coordinated. The components of these systems were integrated and stabilized by cross-linking with genipin, a compound of natural origin. They can be precisely injected into the diseased tissue in the form of a viscous sol or a partially cross-linked hydrogel, where they can serve as scaffolds for locally controlled bone tissue regeneration/remodeling by supporting the osteoblast formation/proliferation and maintaining the optimal osteoclast level. These materials lack systemic toxicity. They can be particularly useful for the repair of small osteoporotic bone defects.

Dielectric studies under various temperature ( T ) and pressure ( p ) conditions on five active pharmaceutical ingredients (APIs) with antifungal properties-itraconazole (ITZ), posaconazole (POS), terconazole (TER), ketoconazole (KET), and fluconazole (FLU)-were carried out. We have thoroughly studied the connection between the pressure coefficient of the glass transition temperature (d T g /d p ) and the activation volume of both relaxation modes (Δ V α , Δ V δ/α' ) with respect to the molecular weight ( M w ) or molar volume ( V m ) in these systems. Besides, high pressure data revealed that the time scale separation between α- and δ- or α'-processes increases with pressure in ITZ and TER. What is more, the activation entropy, which is a measure of cooperativity, calculated from the Eyring model for the secondary (β)-relaxation in ITZ and POS, increased and decreased, respectively, in the compressed samples. To understand these peculiar results, we have carried out X-ray diffraction (XRD) measurements on the pressure-densified glasses and found that pressure may induce frustration in molecular organization and destroy the medium-range order while enhancing the short-range correlations between molecules. This finding allowed us to conclude that varying molecular spatial arrangement is responsible for the extraordinary dynamical behavior of ITZ, POS, and TER at high pressure.

In this paper, broadband dielectric spectroscopy (BDS) has been applied to study the molecular dynamics and crystallization kinetics of the antihyperlipidemic active pharmaceutical ingredient (API), gemfibrozil (GEM), as well as its deuterated (dGEM) and methylated (metGEM) derivatives, characterized by different types and strengths of intermolecular interactions. Moreover, calorimetric and infrared measurements have been carried out to characterize the thermal properties of examined samples and to probe a change in the H-bonding pattern in GEM, respectively. We found that the dielectric spectra of all examined compounds, collected below the glass transition temperature ( T g ), reveal the presence of two secondary relaxations (β, γ). According to the coupling model (CM) predictions, it was assumed that the slower process (β) is of JG type, whereas the faster one (γ) has an intramolecular origin. Interestingly, the extensive crystallization kinetics measurements performed after applying two paths, i.e., the standard procedure (cooling and subsequently heating up to the appropriate temperature, T c ), as well as annealing at two temperatures in the vicinity of T g and further heating up to T c , showed that the annealing increases the crystallization rate in the case of native API, while the thermal history of the sample has no significant impact on the pace of this process in the two derivatives of GEM. Analysis of the dielectric strength (Δε) of the α-process during annealing, together with the results of Fourier transform infrared spectroscopy (FTIR) measurements, suggested that the reorganization within dimeric structures formed between the GEM molecules is responsible for the observed behavior. Importantly, our results differ from those obtained by Tominaka et al. (Tominaka, S.; Kawakami, K.; Fukushima, M.; Miyazaki, A.Physical Stabilization of Pharmaceutical Glasses Based on Hydrogen Bond Reorganization under Sub-T g Temperature Mol. Pharm. 2017 14 264 273 10.1021/acs.molpharmaceut.6b00866.), who demonstrated that the sub- T g annealing of ritonavir (RTV), which is able to form extensive supramolecular hydrogen bonds, protects this active substance against crystallization. Therefore, based on these contradictory reports, one can hypothesize that materials forming H-bonded structures, characterized by varying architecture, may behave differently after annealing in the vicinity of the glass transition temperature.

Cationic derivatives of dextran (Dex) and hydroxypropylcellulose (HPC) were studied as potential alternatives of protamine sulfate (PS) used in the reversal of anticoagulant activity of heparin. The modification was performed by the attachment of cationic groups to the Dex main chain or by grafting short side chains of a polycation onto HPC. The cationic derivatives of these polysaccharides were found to bind heparin with the efficiency increasing with growing degree of cationic modification. The degree of cationic modification and consequently the ζ potential of the polymers do not have to be high to achieve effective heparin binding. The size of the complexes of cationic Dex with unfractionated heparin (UFH) is a few micrometers. For complexes of cationic HPC and UFH the size is much below 1 μm, both below and above the lower critical solution temperature of HPC. None of the cationic polysaccharides studied caused hemolysis. The concentrations of the polymers inducing the aggregation of human erythrocytes in vitro were determined.

In emergency cases anticoagulant action of heparin needs to be stopped instantaneously, which is usually achieved by intravenous administration of protamine sulfate (PS). However, PS shows many adverse effects. The objective of the present work was to find out if chitosan (Ch) and a cationically modified chitosan, N-(2-hydroxypropyl)-3-trimethylammonium chitosan chloride (HTCC), may be applied for heparin reversal. For chitosan the efficiency of unfractionated heparin (UFH) binding decreases with increasing pH while for cationically modified chitosan heparin binding is efficient even for high pH values. Complexation of UFH and low-molecular-weight heparin (LMWH) by cationically modified chitosan in the aqueous solution at pH = 7.4 was studied. Complexes of the modified chitosan with UFH are smaller and of lower dispersity than those with PS. Cationically modified chitosan was found to bind both UFH and LMWH. The complex formation capability of cationically modified chitosan is comparable to that of PS.

Chitosan hydrogel microspheres were obtained by cross-linking chitosan in its inverse emulsion using genipin as cross-linker. The genipin-cross-linked chitosan microspheres (ChGp) swell significantly in water at pH values below 6.5 and shrink to a smaller extent at pH values above 6.5. ChGp microspheres bind heparin in water. The kinetics of heparin binding was found to be pH dependent and was faster and more efficient at a lower pH. That can be also controlled by the weight of ChGp microspheres used. Rate and efficiency of heparin adsorption at pH 7.4, which is typical of blood, could be increased by quaternization of ChGp microspheres using glycidyltrimethylammonium chloride (GTMAC). The polymeric material obtained thus can be potentially useful for heparin removal in biomedical applications.