Molecular Dynamics Simulations of the Adsorption of Bone Morphogenetic Protein-2 on Surfaces with Medical Relevance

Utesch, Tillmann; Daminelli, G.; Mroginski, María Andrea

doi:10.1021/la202489w

Cited by 93 publications

(104 citation statements)

References 56 publications

(88 reference statements)

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“…[32][33][34] The incorporation of bioactive components into other selfassembling biomaterials has been shown to cause structural disruption, which can be directly reflected in the material mechanical properties. 35 Since electrostatic interactions are a key component to collagen-HyA membrane self-assembly, the incorporation of BMP-2, which contains several positively and negatively charged amino acids, 31,36 has the potential to disrupt membrane formation and the structural integrity of the membrane. 35,37 However, SEM images of collagen-HyA membranes with or without BMP-2 incorporation demonstrated no change in the membrane microstructure upon BMP-2 incorporation (Fig.…”

Section: Resultsmentioning

confidence: 99%

Osteogenic Potential of BMP-2-Releasing Self-Assembled Membranes

Chung

Chien

Aguado

et al. 2013

Tissue Engineering Part A

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We report here the use of novel self-assembling collagen-hyaluronic acid (HyA) membranes to deliver bone morphogenetic protein-2 (BMP-2) for orthopedic applications. Prior work has demonstrated that collagen-HyA membranes are formed initially through electrostatic interactions between the oppositely charged collagen and HyA molecules, and that membrane growth is driven by osmotic pressure imbalances between the collagen and HyA solutions. The purpose of this study was to investigate the potential of incorporating charged growth factors such as BMP-2 within the membrane for regenerative medicine applications. Membrane material properties, protein mass loss, and release kinetics of BMP-2, as well as biocompatibility and osteogenic potential in vitro and in vivo using a subcutaneous mouse model were assessed. Scanning electron microscopy and mechanical testing confirmed no loss of structural or mechanical integrity upon BMP-2 incorporation into the membranes. Slow and steady release of the growth factor was demonstrated with 17% of total loaded BMP-2 released over the course of 49 days. To test biocompatibility and osteogenic potential in vitro, human mesenchymal stem cells were cultured on collagen-HyA membranes and showed greater proliferation rates (for up to 28 days) on membranes without BMP-2, but a greater alkaline phosphatase activity and osteocalcin production on membranes releasing BMP-2. In vivo subcutaneous implantation of the membranes showed a minimal immune response with osteoblasts and mineral deposits present in the ectopic site for BMP-2-releasing membranes, further demonstrating the potential of the BMP-2-releasing membranes to induce osteogenic differentiation. This study presents a novel strategy to create self-assembled membranes using two biocompatible molecules that can deliver bioactive agents in a sustained manner to induce a local regenerative response.

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Section: Resultsmentioning

confidence: 99%

Osteogenic Potential of BMP-2-Releasing Self-Assembled Membranes

Chung

Chien

Aguado

et al. 2013

Tissue Engineering Part A

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“…Particularly, SMD simulations conducted to investigate the effect of the tip of an AFM showed that pushing a molecule towards a surface with an AFM tip will bias the results by increasing adhesion, as the force exerted on the molecule leads it to spread more on the surface (Horinek et al 2008;Mücksch & Urbassek, 2011). With SMD simulations, the adsorption mechanisms of peptides and proteins on different types of surfaces have been investigated (Alvarez-Paggi et al 2010;Dong et al 2007;Emami et al 2014b;Friedrichs et al 2013;Hamdi et al 2008;Shen et al 2008;Utesch et al 2011;Yang & Zhao, 2007) and compared with experimental measurements (Schneider & Colombi Ciacchi, 2010. In addition to accelerating the sampling of certain events, the SMD method is used to calculate free energy differences.…”

Section: Non-equilibrium Methodsmentioning

confidence: 99%

“…Non-covalent binding processes can be described within a MM framework, which drastically reduces computational costs compared with QM, and thus enables the simulation of the dynamics of systems that consist of millions of atoms for up to microseconds with solvent molecules modeled explicitly. All-atom MM simulations are important, in particular, for investigation of the dynamic and thermodynamic properties of protein adsorption (Mahmoudi et al 2011;Utesch et al 2011). The nano length scale is usually appropriate for studying protein-surface interactions at the molecular level, and hence, all-atom simulations are common methods of choice (Gagner et al 2012).…”

Section: Morphologymentioning

confidence: 99%

“…Capturing the time and length scales of a complete adsorption process therefore necessitates employing mesoscopic, coarse-grained (CG) and multiscale approaches (Gray, 2004;Wei et al 2011). Furthermore, hybrid approaches such as QM/MM to bridge typical time and length scales of conventional approaches, and enhanced sampling simulation techniques to accelerate adsorption and desorption events have been proposed and successfully applied to study protein-inorganic surface interactions (Euston et al 2008;Utesch et al 2011;Zhang & Sun, 2010).…”

Section: Morphologymentioning

confidence: 99%

See 1 more Smart Citation

Modeling and simulation of protein–surface interactions: achievements and challenges

Ozboyaci

Kokh

Corni

et al. 2016

Quart. Rev. Biophys.

180

191

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Abstract. Understanding protein-inorganic surface interactions is central to the rational design of new tools in biomaterial sciences, nanobiotechnology and nanomedicine. Although a significant amount of experimental research on protein adsorption onto solid substrates has been reported, many aspects of the recognition and interaction mechanisms of biomolecules and inorganic surfaces are still unclear. Theoretical modeling and simulations provide complementary approaches for experimental studies, and they have been applied for exploring protein-surface binding mechanisms, the determinants of binding specificity towards different surfaces, as well as the thermodynamics and kinetics of adsorption. Although the general computational approaches employed to study the dynamics of proteins and materials are similar, the models and force-fields (FFs) used for describing the physical properties and interactions of material surfaces and biological molecules differ. In particular, FF and water models designed for use in biomolecular simulations are often not directly transferable to surface simulations and vice versa. The adsorption events span a wide range of time-and length-scales that vary from nanoseconds to days, and from nanometers to micrometers, respectively, rendering the use of multi-scale approaches unavoidable. Further, changes in the atomic structure of material surfaces that can lead to surface reconstruction, and in the structure of proteins that can result in complete denaturation of the adsorbed molecules, can create many intermediate structural and energetic states that complicate sampling. In this review, we address the challenges posed to theoretical and computational methods in achieving accurate descriptions of the physical, chemical and mechanical properties of protein-surface systems. In this context, we discuss the applicability of different modeling and simulation techniques ranging from quantum mechanics through all-atom molecular mechanics to coarse-grained approaches. We examine uses of different sampling methods, as well as free energy calculations. Furthermore, we review computational studies of protein-surface interactions and discuss the successes and limitations of current approaches.

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“…[28][29][30] In addition, GOs' hydrophobic domains can interact with those of proteins' by hydrophobic π-π stacking. [31][32][33] Therefore, GO can allow for a sustained release of loaded protein, which is critical for clinical use of protein delivery. In this study, we delivered both BMP-2 and SP using GO-coated Ti to further promote bone formation compared with BMP-2 delivery using GO-coated Ti.…”

Section: Introductionmentioning

confidence: 99%

Delivery of bone morphogenetic protein-2 and substance P using graphene oxide for bone regeneration

La¹,

Jin²,

Park³

et al. 2014

IJN

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In this study, we demonstrate that graphene oxide (GO) can be used for the delivery of bone morphogenetic protein-2 (BMP-2) and substance P (SP), and that this delivery promotes bone formation on titanium (Ti) implants that are coated with GO. GO coating on Ti substrate enabled a sustained release of BMP-2. BMP-2 delivery using GO-coated Ti exhibited a higher alkaline phosphatase activity in bone-forming cells in vitro compared with bare Ti. SP, which is known to recruit mesenchymal stem cells (MSCs), was co-delivered using Ti or GO-coated Ti to further promote bone formation. SP induced the migration of MSCs in vitro. The dual delivery of BMP-2 and SP using GO-coated Ti showed the greatest new bone formation on Ti implanted in the mouse calvaria compared with other groups. This approach may be useful to improve osteointegration of Ti in dental or orthopedic implants.

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Molecular Dynamics Simulations of the Adsorption of Bone Morphogenetic Protein-2 on Surfaces with Medical Relevance

Cited by 93 publications

References 56 publications

Osteogenic Potential of BMP-2-Releasing Self-Assembled Membranes

Osteogenic Potential of BMP-2-Releasing Self-Assembled Membranes

Modeling and simulation of protein–surface interactions: achievements and challenges

Delivery of bone morphogenetic protein-2 and substance P using graphene oxide for bone regeneration

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