162 research outputs found

    Modelling the molecular mechanisms of biocompatibility of artifical materials

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    One of the most common reasons for implant failure is immune rejection. Implant rejection leads to additional surgical intervention and, ultimately, increases health cost as well as recovery time. Within a few hours after implantation, the implant surface is covered with host proteins. Adsorption of fibrinogen, a soluble plasma glycoprotein, is responsible in triggering the immune response to a given material and, subsequently, in determining its biocompatibility. The work presented here is focused on modeling the interaction between artificial surfaces and plasma proteins at the microscopic level by taking into account the physico-chemical properties of the surfaces. Carbon-based nanomaterials are chosen as a model system due to their unique bioadhesive and contradictory biocompatible properties as well as the possibility of functionalization for specific applications. Graphene and its derivatives, such as graphene oxide and reduced graphene oxide, demonstrate controversial toxicity properties in vitro as well as in vivo. In this study, by covalently adding chemical groups, the wettability of graphene surfaces and the subsequent changes in its biocompatibility are being examined. An empirical force field potential (AMBER03) molecular dynamic simulation code implemented in the YASARA software package was utilized to model graphene/biomolecule interactions. The accuracy of the force field choice was verified by modeling the adsorption of individual amino acids to graphene surface in a vacuum. The obtained results are in excellent agreement with previously published ab initio findings. In order to mimic the natural protein environment, the interaction of several amino acids with graphene in an explicit solvent was modeled. The results show that the behaviour of amino acids in aqueous conditions is drastically different from that in vacuum. This finding highlights the importance of the host environment when biomaterial-biomolecule interfaces are modeled. The surface of Graphene Oxide (GO) has been shown to exhibit properties that are useful in applications such as biomedical imaging, biological sensors and drug delivery. An assessment of the intrinsic affinity of amino acids to GO by simulating their adsorption onto a GO surface was performed. The emphasis was placed on developing an atomic charge model for GO that was not defined before. Next, the simulation of a fibrinogen fragment (D-domain) at the graphene surface in an explicit solvent with physiological conditions was performed. This D-domain contains the hidden (not expressed to the solvent) motifs (PI 7190-202 and P2 7377-395, and specifically P2-C portion 7383-395) that were experimentally found to be responsible for attracting inflammatory cells through CDllb/CD18 (Mac-1) leukocyte integrin and, consequently, promoting the cascade of immune reactions. It was hypothesized that the hydrophobic nature of graphene would cause critical changes in the fibrinogen D-domain structure, thus exposing the sequences and result in the foreign body reaction. To further study this issue, molecular mechanics was used to stimulate the interactions between fibrinogen and a graphene surface. The atomistic details of the interactions that determine plasma protein affinity modes on surfaces with high hydrophobicity were studied. The results of this work suggest that graphene is potentially pro-inflammatory surface, and cannot be used directly (without alterations) for biomedical purposes. A better understanding of the molecular mechanisms underlying the interaction between synthetic materials and biological systems will further the ultimate goal of understanding the biocompatibility of existing materials as well as design of new materials with improved biocompatibility

    A health concern regarding the protein corona, aggregation and disaggregation

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    Nanoparticle (NP)-protein complexes exhibit the correct identity of NP in biological media. Therefore, protein-NP interactions should be closely explored to understand and to modulate the nature of NPs in medical implementations. This review focuses mainly on the physicochemical parameters such as dimension, surface chemistry, the morphology of NPs and influence of medium pH on the formation of protein corona and conformational changes of adsorbed proteins by different kinds of methods. Also, the impact of protein corona on the colloidal stability of NPs is discussed. Uncontrolled protein attachment on NPs may bring unwanted impacts such as protein denaturation and aggregation. In contrast, controlled protein adsorption by optimal concentration, size, pH and surface modification of NPs may result in potential implementation of NPs as therapeutic agents especially for disaggregation of amyloid fibrils. Also, the effect of NPs-protein corona on reducing the cytotoxicity and clinical implications such as drug delivery, cancer therapy, imaging and diagnosis will be discussed. Validated correlative physicochemical parameters for NP-protein corona formation frequently derived from protein corona fingerprints of NPs which are more valid than the parameters obtained only on the base of NP features. This review may provide useful information regarding the potency as well as the adverse effects of NPs to predict their behavior in the in vivo experiments.Comment: 40 pages, 20 figure

    Graphene-VP40 interactions and potential disruption of the Ebola virus matrix filaments

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    Ebola virus infections cause hemorrhagic fever that often results in very high fatality rates. In addition to exploring vaccines, development of drugs is also essential for treating the disease and preventing the spread of the infection. The Ebola virus matrix protein VP40 exists in various conformational and oligomeric forms and is a potential pharmacological target for disrupting the virus life-cycle. Here we explored graphene-VP40 interactions using molecular dynamics simulations and graphene pelleting assays. We found that graphene sheets associate strongly with VP40 at various interfaces. We also found that the graphene is able to disrupt the C-terminal domain (CTD-CTD) interface of VP40 hexamers. This VP40 hexamer-hexamer interface is crucial in forming the Ebola viral matrix and disruption of this interface may provide a method to use graphene or similar nanoparticle based solutions as a disinfectant that can significantly reduce the spread of the disease and prevent an Ebola epidemic

    Protein adsorption on nanostructured polymer surfaces

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    Human plasma fibrinogen (HPF) plays an essential role in the initial host response to biomaterials. Developing strategies for controlling the HPF biomaterial interactions is crucial but is still in its infancy. Here, it was demonstrated that the nanostructures on polymers such as needle like crystals (NLCs) and lamellar crystals (LCs) of isotactic polybutene 1 (iPB 1), as well as shish kebab crystals (SKCs) of high density polyethylene (HDPE), were capable of guiding the adsorption of HPF and their subsequent platelet adhesion. The NLCs of iPB 1, with a lateral dimension lower than the length of the HPF major axis, supported side on adsorption and trinodular conformation, confirmed by atomic force microscopy and quartz crystal microbalance with dissipation. Preferential alignment of HPF molecules concerning the axial direction of the NLCs was analyzed via an orientation analysis performed on single and multi protein levels. The results of the protein adsorption kinetic studies via quartz crystal microbalance revealed the surface dependent packing density and assembly configuration of HPF. To elucidate the relationship between single HPF adsorption and HPF layer formation, the dynamics of HPF assemblies adsorbed on nanostructured surfaces were investigated in situ by mapping using accumulated probe trajectories. Anisotropic diffusion of HPF was revealed on NLCs. This was ascribed to the partial detachment and thus the Sansetsukon like nanocrawling of HPF. To further understand the biofunctionality of the surface immobilized HPF, platelet adhesion as a function of surfaces and conformation was investigated. It was observed that the number of platelets adhered on NLCs was significantly reduced by 90% after one hour incubation, compared with those on LCs and SKCs. NLCs led to small platelet aggregates, which point toward the potential thrombogenicity of such nanostructured surfaces

    Mechanistic Understanding From Molecular Dynamics Simulation in Pharmaceutical Research 1 : Drug Delivery

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    In this review, we outline the growing role that molecular dynamics simulation is able to play as a design tool in drug delivery. We cover both the pharmaceutical and computational backgrounds, in a pedagogical fashion, as this review is designed to be equally accessible to pharmaceutical researchers interested in what this new computational tool is capable of and experts in molecular modeling who wish to pursue pharmaceutical applications as a context for their research. The field has become too broad for us to concisely describe all work that has been carried out; many comprehensive reviews on subtopics of this area are cited. We discuss the insight molecular dynamics modeling has provided in dissolution and solubility, however, the majority of the discussion is focused on nanomedicine: the development of nanoscale drug delivery vehicles. Here we focus on three areas where molecular dynamics modeling has had a particularly strong impact: (1) behavior in the bloodstream and protective polymer corona, (2) Drug loading and controlled release, and (3) Nanoparticle interaction with both model and biological membranes. We conclude with some thoughts on the role that molecular dynamics simulation can grow to play in the development of new drug delivery systems.Peer reviewe
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