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.