Inorganic Nanoparticles as Protein Mimics

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Science  08 Oct 2010:
Vol. 330, Issue 6001, pp. 188-189
DOI: 10.1126/science.1190094

Water-soluble inorganic nanoparticles (NPs) and globular proteins (GPs) might seem “as different as chalk and cheese,” especially in the interior. The chemical structure of GPs is usually exact and well-defined, whereas NPs are almost always formed as a mixture of sizes and variation of shapes. The complexity and dynamism of three-dimensional atomic organization inside the protein globules and related functionalities are not present in the impenetrable crystalline cores of NPs. However, NPs and GPs do reveal similarities in overall size, charge, and shape, and the exterior surfaces of NPs can be coated with organic functional groups similar to those exposed by GPs, which suggest that NPs could function as protein mimics. This option is attractive because NPs are usually cheaper and more stable than proteins, but can they actually display the same functionalities and achieve enough specificity to replace proteins?

The majority of preparation schemes of water-soluble NPs use thin coatings of small organic molecules, or stabilizers, with a variety of functional groups and some degree of anisotropy (1). The methods for separating, purifying, and solubilizing NPs and GPs are similar (24). Typical sizes of NPs and GPs are comparable to nanometer-scale features of cellular membranes, such as ion channels (5). The interactions of water-soluble NPs and GPs with the environment and other soluble molecules are virtually identical and depend on the same media parameters. For example, surface charges of both NPs and GPs depend on pH and ionic strength and can influence their binding interactions to cellular membranes (5). If needed, the NP coatings may also include larger molecules, such as cyclodextrins or peptides, in which case they resemble GPs that bear sugars, lipids, and other groups added by posttranslational modification.

Nanoparticles vie for protein jobs.

Examples of (A) demonstrated, (B) partially demonstrated, and (C) potential functional similarities between water-soluble nanoparticles and globular proteins.


To what extent has similarity in surface properties led to analogs of biological functions? Some of these functions can indeed be found for NPs (see the figure, panel A). For instance, analogs of the bimolecular GroEL protein complex were found in cadmium selenide, gold, and nickel-palladium NPs (6). Bayraktar et al. observed formation of pair complexes of gold NPs with cytochrome c and cytochrome c peroxidase (3). Tuning the size and the charge should make it possible for the NP spheres to mimic either the cylindrical channel of GroEL or the semispherical binding patch of cytochrome c peroxidase.

Enzymatic activity has been observed in the NPs developed by Scrimin and co-workers, which have stabilizers including peptides forming a complex shell. For instance, successful hydrolysis of a phosphate bond of phosphodiesters to create a functional replica of a ribonuclease can be achieved (7), and gold NPs modified with beta-cyclodextrin possessed esterase activity (8).

Recent studies also indicate that NPs can self-assemble into complex microscale superstructures such as chains, sheets, and twisted ribbons (911). Parallels can be made with GPs such as amelogenin (12) assembling in chains, S-layer proteins and chaperonin assembling in two-dimensional sheets (13), and GPs in the capsid of tobacco mosaic virus forming helical tubules (14). The accurate description of the self-assembly process was also achieved in computer simulations that incorporated force fields around the NPs similar to those used previously for proteins (9, 15). The similarity of the chemical behavior of NPs and GPs is not accidental but is based on analogous structure as well as thermodynamic and kinetic behavior of nanoscale structures in aqueous media.

Other emblematic functions of GPs have also been identified in recent publications but with lower degrees of experimental proof and functional resemblance (see the figure, panel B). For example, proteins can facilitate transport of DNA across cellular membranes. Bharali et al. found that NPs can efficiently do the same and cross cellular membranes themselves (16). They can support transfection of cells with genes replicating the function of bacterial SpoIIIE protein (17). The positive charge of the NPs and tight coiling of DNA around them resemble histone-DNA inter actions and may account for the high efficiency of NPs as transfection vectors. Formation of extensive networks of NPs or gels (18) can be compared with structural function of different proteins, but adequate replication of gel and network formation will require the demonstration of the reversibility of such reactions and different mechanical properties of the gels. Proteins perform a variety of functions when bound to DNA. Such binding occurs with NPs but without specificity (19).

It should be possible to replicate other functions of GPs that depend mainly on surface interactions by using NPs (see the figure, panel C). A logical extension of previous works is molecular engineering of the NP surface to reach specific and reversible binding of both small and large biomolecules, including DNA. These functions can find extensive use in biotechnology to control pathways of bacterial biosynthesis with NPs. Nanoscale systems with dynamic stimuli-responsive NP networks will lead to new sensing platforms and fluids with unusual flow responses reminiscent of many biological fluids. NP interactions with membrane receptors might have produced cell signaling events, but these effects remain to be investigated systematically (20, 21). Another potentially prolific direction is NP design to perform chiral catalysis and inhibition of specific enzymes. If these functionalities are realized, they should enable medically relevant drug design, as well as clarifying the health effects of NPs present in the environment.


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