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Molecular Understanding and Design of Zwitterionic Materials Qing Shao and Shaoyi Jiang*

losing the bioactivity,[12] and induce no immunological response in vivo in blood circulation.[13] These studies highlight the essential roles of zwitterionic materials in solving many critical problems. Zwitterions are widely spread in nature, including osmolytes,[14] cell membranes,[15] and proteins. The first successful synthesis of zwitterionic materials was reported in 1950s.[16] Since then, many studies have been performed on the synthesis and solution properties of zwitterionic materials and their applications. The review by Lowe and McCormick[4] has summarized the synthesis and solution properties of zwitterionic materials. The biological applications of zwitterionic materials and surfaces have been under study for a long time, but the mechanisms of their performances are not well known. Ishihara et al.[17] showed that zwitterionic 2-methacryloyloxyethyl phosphorylcholine (MPC) polymers could function as a protein-adsorption-resistant additive. The ability of MPC materials to reduce protein adsorption was attributed to their similarities in chemical structures to the head group of PC lipids in cell membranes. Chen et al.[18] demonstrated that the key to the resistance of zwitterionic materials to nonspecific protein adsorption is their zwitterionic feature that results in strong electrostatically induced hydration. He et al.[19] further showed from molecular simulations that zwitterionic PC self-assembled monolayers (SAMs) are highly resistant to nonspecific protein adsorption due to their strong hydration properties. These results were consistent with those from earlier studies of poly(ethylene glycol) (PEG) materials, which are resistant to nonspecific protein adsorption due to their strong hydration via hydrogen bonding. Based on the molecular mechanism of nonspecific protein adsorption resistance of zwitterionic materials and earlier studies by Whitesides and co-workers,[20] carboxybetaine (CB) and sulfobetaine (SB) materials were demonstrated to be super low fouling (CB– Na+>CB–K+>CB–Cs+ (Figure 6b). For instance, the lifetime of CB–Na+ associations is 30-fold greater than that of CB–K+ associations. The SB–ion interactions are not as sensitive as the CB–ion interaction. The results of second type of simulation system confirmed that CB–cation interactions are more sensitive to the cation type than SB–cation interactions. In the case of a cation selecting between CB and SB moieties, as in the third type of systems, simulation results showed that kosmotropic cations prefer CB moieties and chaotropic cations prefer SB moieties (Figure 6c). The sulfonate group of SB moiety has less charge density than the carboxylic group of CB moiety. Therefore, it may be more preferred by the chaotropic cations, which also have low charge densities. The charge densities of charged groups not only influence the zwitterion–ion interactions, but also influence the associations among zwitterionic moieties themselves, which will be summarized in the next section. 3.3. Differences between CB and SB Moieties: Self-Associations Zwitterionic moieties can associate among themselves through the interactions between cationic and anionic groups. These

Adv. Mater. 2014, DOI: 10.1002/adma.201404059

Figure 6. Difference between CB and SB moieties in ionic interactions. a) The simulation configuration, b) the association numbers of CB and SB moieties with cations in the presence of different anions, and c) the difference in the lifetimes between the CB cation association and SB cation association for Na+, K+, and Cs+. The CB cation association is sensitive to the type of cation, and the SB cation association is not sensitive to the type of cation. The type of anions does not influence the sensitivity. CB moieties associate with kosmotropic cations stronger than SB moieties do, whereas CB moieties associate with chaotropic cations weaker than SB moieties do. Reprinted with permission.[43] Copyright 2011, American Chemical Society.

self-associations cause zwitterionic materials to have both lower critical solution temperature and upper critical solution temperature,[44] antipolyelectrolyte effects,[45] stimuli responses,[44] and even hydrophobic properties. [46] The

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Figure 7. Difference between CB and SB materials in associations among zwitterionic moieties. a) Schematic demonstration that the charge–density difference determines the association among zwitterionic moieties, b) rheology moduli of CB materials, c) rheology moduli of SB materials, d) hydrodynamic size of CB polymer and SB polymer solutions (2 g L–1) as a function of NaCl concentration, e) simulation configuration of zwitterionic polymers, f) radial distribution functions (RDFs) between oxygen atoms and nitrogen atoms of CB and SB polymers, g) residence curves of associations among zwitterionic moieties of CB and SB polymers, h) simulation configuration of small zwitterionic molecules, i) RDFs between oxygen atoms and nitrogen atoms of small SB molecules, and j) RDFs between oxygen atoms and nitrogen atoms of small CB molecules. The experiments showed that SB polymers are thermal and salt responsive, whereas CB polymers are not. Simulation studies showed that this is because SB moieties self-associate, whereas CB moieties do not. The different associations originated from the difference in charge densities of charged groups. Reprinted with permission.[47] 2014, American Chemical Society.

classical theory of zwitterionic materials assumes that the selfassociations exist in all zwitterionic materials.[45] However, CB polymers do not show thermal or salt responses that should be caused by the self-associations among zwitterionic moieties,[47] whereas SB polymers did (Figure 7b–d). In order to study the

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origin, Shao et al.[47] simulated the aggregation of CB and SB polymers in water using MD simulations. To exactly represent the molecular structure of zwitterionic polymers used in experiments, the CB polymers have zwitterionic moieties with two methylene groups between the charged groups and the

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PROGRESS REPORT Figure 8. Influence of distance between charged group on molecular properties of CB moieties. a) Electrostatic potential surfaces of CB moieties, b) hydration free energy of CB moieties, c) distributions of cosθ (θ is the angle between the dipole moment of water molecules and the OCB–Owater line), d) lifetimes of water molecules in the hydration shells of carboxylic groups of CB moieties, e) RDFs between oxygen atoms of CB moieties and Na+, and f) association lifetime of CB–Na+ association for CB moieties. Reprinted with permission.[49] Copyright 2013, American Chemical Society.

SB polymers have zwitterionic moieties with three methylene groups (Figure 1). They found that the cationic and anionic groups of CB moieties do not form many associations, disobeying the classical theory of zwitterions (Figure 7e–g). The distance between charged groups does not influence this association qualitatively (Figure 7h–j). Further analysis indicates that the self-associations among zwitterionic moieties should originate from the charge density difference of cationic and anionic groups. Fennell et al.[48] showed that the hydration similarity of ions determines the ion–ion associations. The selfassociations among zwitterionic moieties were also dictated by similarity in their charge densities. This finding implies the distinctive characters of CB and SB materials and their applications. CB materials own the strongest hydration and few self-associations. Therefore, they are able to resist nonspecific protein adsorption even in complex media and be nearly inert to changes in environmental parameters. SB materials exhibit strong hydration and moderate self-associations. Thus, they can resist nonspecific protein adsorption and have external stimuli properties.

4. Chemical Groups between Charged Groups Besides the cationic and anionic groups, the chemical groups between the charged groups influence properties of zwitterionic moieties. They determine the distance between the charged groups, and their chemistries can also tune the material properties. This section will summarize two simulation

Adv. Mater. 2014, DOI: 10.1002/adma.201404059

and modeling studies addressing the chemical groups between charged groups: one describes the influence of distance between charged groups on properties of CB moieties[49] and the other describes the influence of their chemistries on the mechanical properties of zwitterionic hydrogels.[50]

4.1. Distance between Charged Groups Using molecular simulations and quantum chemical calculations, Shao and Jiang[49] studied the charge distribution, hydration and, ionic interactions of CB moieties containing zero to four methylene groups. They found that the influence of distance between charged groups only occurs in short range and it is significant. Their quantum chemical calculations showed that the partial charges of the carboxylic group in a CB moiety with one methylene group are much less than that in a CB moiety with three methylene groups (Figure 8a). This is due to the interference between cationic and anionic groups and explains why the carboxylic group of glycine betaine has a pKa much lower than that of acetic acid.[51] MD simulation results showed that such variation of partial charges also influence the hydration structure and dynamics of the carboxylic groups (Figure 8c,d). The water molecules in the hydration shell of the carboxylic group of a CB moiety with one methylene group have lower residence time and wider dipole-orientation distribution than those in the hydration shell of the carboxylic group of a CB moiety with three methylene groups. The hydration of the cationic groups does not change significantly, indicating

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that the carboxylic group is more vulnerable to the distance between charged groups than the cationic group. Interactions between ions and CB moieties are also strongly dependent on the distance between charged groups (Figure 8e,f). In this same work, Shao et al. studied the structure, dynamics, and free energy surfaces of CB–Na+ associations using MD and well-tempered metadynamics simulations. They found that the CB–Na+ associations follow the similar trend as the hydration of the carboxylic groups of CB moieties but their variation as a function of the distance between charged groups is more sensitive than the latter, likely because the CB–Na+ interactions are affected by electrostatic interactions. This sensitivity dependence can induce some distinctive performance of various CB materials. For instance, Mi et al.[52] showed that CB materials with one methylene group do not associate with Mg2+ and therefore can resist sugar fouling, whereas CB materials with two methylene groups have some fouling because of their interactions with Mg2+.

4.2. Chemistry of Chemical Groups between Charged Groups In addition to tuning the distance between charged groups, the chemical groups between cationic and anionic may interact with the charged groups and affect certain properties of zwitterionic materials. He et al.[50] studied the mechanical properties of two zwitterionic CB hydrogels with or without a hydroxyl group in the spacer region between the charged groups using MD simulations. The hydroxyl groups can add the hydrophilicity of the polymer chains and result in two possible scenarios. If these hydroxyl groups primarily attract water molecules, the water content of the hydrogels will increase, resulting in a possible decrease in mechanical properties. If these hydroxyl groups primarily interact with other charged groups of polymers, it may enhance the inter- and intrachain interactions in polymers, resulting in an increase in mechanical properties. He et al.[50] studied the stress modulus of CB hydrogels with and without hydroxyl groups as a function of strain. They found that the hydroxyl groups primarily associate with the charged groups of CB hydrogels. Consequently, CB hydrogels with hydroxyl groups have less water content than the CB hydrogels without hydroxyl groups with the same number of cross-linker and a higher stress modulus under the same strain (Figure 9b). This study demonstrated how the properties of zwitterionic materials can be well tuned by alternating the chemical groups between the charged groups.

5. Molecular Design of Protein-Resistant Zwitterionic Moieties beyond Conventional CB and SB The studies summarized above investigated the differences between zwitterionic and nonionic materials and the differences among zwitterionic materials. The following studies showed that in order to assess the protein-resistant ability of zwitterionic materials at least three criteria should be considered: hydration, self-associations among zwitterionic moieties,

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Figure 9. Influence of chemistry between chemical groups between charged groups on mechanical properties of CB hydrogels. a) Molecular structures of pCBMA and OH-pCBMA, b) stress of the two hydrogels as a function of strain, and c) the snapshot of the OH-pCBMA hydrogels system. Reprinted with permission.[50] 2012, American Chemical Society.

and protein interactions. Strong hydration was once the only property believed to relate to the protein-resistant capability of materials.[28] However, the studies above showed that we must consider the other two properties when assessing

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PROGRESS REPORT Figure 10. Molecular design of protein-resistant zwitterionic moieties beyond CB and SB moieties. Molecular structures of 12 zwitterionic moieties. These moieties were derived from three anionic groups and four cationic groups widely present in nature, and three properties to assess the proteinresistant capability of zwitterionic moieties: hydration, self-association, and protein interactions. The zwitterionic moieties need to have strong hydration to generate repulsive force against protein adsorption, requiring few to moderate self-associations such that most zwitterionic moieties can provide strong hydration instead of associating among themselves and few protein interactions to avoid specific protein binding. Reprinted with permission.[54] 2014, American Chemical Society.

protein-resistant materials, particularly zwitterionic materials. Single zwitterionic moieties may have strong hydration; however, the strong self-associations among zwitterionic moieties may make it very difficult to retain strong hydration in zwitterionic polymers. A typical example is that many SB moieties can cause materials to acquire hydrophobic properties[46] while proteins are rich in charged groups.[53] Any specific interactions between the charged groups of proteins and zwitterionic moieties could compromise the protein-resistant ability of materials. In this section, we introduce a molecular study to design new zwitterionic moieties beyond conventional CB and SB materials using these three criteria. Shao and Jiang[54] derived 12 zwitterionic moieties from three anionic groups and four cationic groups, which are common in natural compounds, and studied their hydration, self-association, and protein interactions using molecular simulations (Figure 10). They studied the hydration of the 12 zwitterionic moieties from free energy, structure, and dynamic aspects. Simulation results showed that, though the hydration structure and dynamics of individual zwitterionic moieties may vary, all 12 zwitterionic moieties have very low hydration free energy, indicating strong hydration. Thus, all 12 zwitterionic moieties may have good protein-resistant capability simply from a hydration aspect. However, further studies on self-associations and protein interactions screen out several candidates. A good candidate for protein resistance needs to have few or moderate self-associations. Only seven zwitterionic moieties show self-associations that fulfill the criterion, including those

Adv. Mater. 2014, DOI: 10.1002/adma.201404059

with a quaternary ammonium group or a tertiary ammonium group and the zwitterionic moiety possessing a carboxylic group and a secondary ammonium group. Among them, the zwitterionic moieties with a quaternary ammonium group are already well known for their protein-resistant capability. White and Jiang showed that zwitterionic glycine with primary amine associates at higher concentrations, decreasing its hydration.[55] The protein interaction studies further screen out the zwitterionic moiety with a sulfate group because the sulfate group may specifically interact with charged groups of proteins. Therefore, besides three zwitterionic moieties with a quaternary ammonium, three other zwitterionic moieties (the one having a tertiary ammonium group and a carboxylic group, the one having a tertiary ammonium group and a carboxylic group, and the one having a secondary ammonium group and a carboxylic group) may have good protein-resistant capability. One of them has been verified in our recent experiments.[56]

6. Summary Zwitterionic materials have paved a way to develop new materials for specific biological applications due to their ability to resist nonspecific protein adsorption in complex media. A thorough understanding of zwitterionic materials from their molecular structures helps to explain the unique properties and phenomena of existing zwitterionic materials and design new zwitterionic materials with specific properties. This report

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summarizes simulation and modeling studies that reveal the relationships between the unique properties of zwitterionic materials and their molecular structures. These studies showed that the distinctive performance of zwitterionic materials embedded from their “zwitterionic” feature, which makes them superhydrophilic. Also, a slight variation in molecular structure can result in significant change of molecular properties and lead to different applications. The variation of physicochemical properties of backbone and linkers may also influence the flexibility and mechanical properties of materials. But the functions of materials should be dictated by the zwitterionic moieties. The nonspecific protein resistance of zwitterionic materials also sets a good starting point for further exploring their potentials. One future direction is to explore naturally occurring zwitterions and develop more zwitterionic materials derived from them. There are many zwitterions in nature and each has its unique functions. If we fully understand their structure–function relationships, we will be able to take advantages of their unique properties and develop new biomaterials in a way never achieved previously.

Acknowledgements This work was supposed by the National Science Foundation (CBET1264477, CMMI-1301435, and DMR-1264470) and the Office of Naval Research (N00014-14-1-0090). The authors thank Erik Liu for proofreading the manuscript and helpful discussion. Received: September 3, 2014 Revised: October 4, 2014 Published online:

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Molecular understanding and design of zwitterionic materials.

Zwitterionic materials have moieties possessing cationic and anionic groups. This molecular structure leads to unique properties that can be the solut...
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