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. Author manuscript; available in PMC: 2009 Dec 1.
Published in final edited form as: Curr Opin Chem Biol. 2008 Sep 5;12(6):722–729. doi: 10.1016/j.cbpa.2008.08.009

Artificial β-Sheets: Chemical Models of β-Sheets

Omid Khakshoor 1, James S Nowick 1
PMCID: PMC2646360  NIHMSID: NIHMS87036  PMID: 18775794

Abstract

Chemical models provide tools with which to simplify and study complicated biological systems. Forces and chemical processes that govern the structure, function, and interactions of a biomacromolecule can be explored with a simple, easy-to-study synthetic molecule. Chemical models of β-sheet structures have helped to elucidate the factors influencing protein structures and functions. Chemical models that mimic β-sheet quaternary structure and interactions are emerging as valuable tools with which to better understand and control protein recognition and protein aggregation.

Introduction

Protein β-sheet structures are formed by the lateral alignment of β-strands in parallel or antiparallel orientations and are stabilized by hydrogen bonding, hydrophobic interactions, and other forces (Figure 1). While intramolecular β-sheet interactions are associated with protein folding, intermolecular β-sheet interactions are associated with protein quaternary structure, protein-protein interactions, and peptide and protein aggregation. Not only are β-sheets important for normal biological activities, but also they are involved in many diseases including HIV, cancer, and neurodegenerative diseases. Recognizing the forces that contribute to the stability and interactions of β-sheets is essential to understanding and controling protein functions and interactions [1,2].

Figure 1.

Figure 1

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Naturally occurring β-sheet structures and interactions.

Model systems that fold to form β-sheet-like structures or participate in intermolecular β-sheet interactions provide valuable tools to study β-sheet folding and interactions. β-Sheet folding has been studied extensively with β-hairpins and related structures [3,4,5,6,7]. Despite the importance of intermolecular β-sheet interactions, few model systems have focused on mimicking these interactions [8,9,10,11]. Artificial β-sheets are chemical models of β-sheets that contain unnatural prosthetic templates. In artificial β-sheets, β-turn mimics, β-strand mimics, and other templates help nucleate and stabilize β-sheet structures or enforce intermolecular β-sheet interactions [12,13,14,15].

This review summarizes the development of artificial β-sheets during the past two years and focuses on those that demonstrate hydrogen-bonding patterns similar to parallel or antiparallel β-sheet structures. The first two sections focus on β-sheet folding; the last two sections focus on intermolecular β-sheet interactions. This review excludes β-turn mimics and β-strand mimics that have not been incorporated into artificial β-sheets. It also excludes synthetic β-hairpins that mimic important side-chain interactions of biologically active peptides and proteins, which were recently reviewed by Robinson [16•].

β-Hairpins containing β-turn mimics

Reverse turns induce β-sheet structure in proteins by aligning protein chains. β-Turn mimics have been used extensively to nucleate β-sheet folding in β-hairpins.

Achiral α-aminoisobutyric acid (Aib) induces a β-turn conformation when combined with either a D-α-amino acid or an achiral α-amino acid. Balaram and coworkers had previously shown that Aib-DAla forms a β-turn structure in the solid state when incorporated into a peptide sequence [17]. The authors have recently shown that the conformation of peptides with a central Aib-Xaa (Xaa = DAla, DVal, DPro, or Gly) unit in solution depends on the solvent: Aib-DAla and Aib-Gly units adopt a β-turn conformation in hydrogen-bonding organic solvents and a helical conformation in organic solvents that do not participate significantly in hydrogen bonding. Aib-DPro and Aib-DVal units, on the other hand, adopt a β-turn conformation in both hydrogen-bonding and non-hydrogen-bonding organic solvents [18]. Hammer, Veglia, Barany, and coworkers have shown that both Aib-DAla and Aib-Gly adopt a β-turn conformation in water [19]. The authors have compared the conformation of one of Gellman’s peptides [20] with three different turn units: Gellman’s DPro-Gly, Balaram’s Aib-DAla, and achiral Aib-Gly (Figure 2A). These peptides all fold into superimposable β-hairpin structures in water. Collectively, these findings show that achiral turn units, like chiral turn units with appropriate chirality, can induce β-hairpin folding.

Figure 2.

Figure 2

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β-Hairpins containing β-turn mimics. (A) β-Hairpins with Aib-based or DPro-Gly turn units. (B) β-Hairpins with extended α,β, α,γ, and α,δ turn units. (C) Light-controlled β-hairpin with azobenzene-based turn unit. (D) β-Hairpin with 1,2,3-triazole-based turn unit. (E) β-Hairpin with tetrahydroisoquinoline-based turn unit. (F) β-Hairpin with diketopiperazine-based turn unit. (G) Parallel β-sheet based on DPro-DADME diamine turn unit. (H) Parallel β-sheet based on CHDA-Gly diacid turn unit.

Balaram and coworkers have reported several expanded β-turn mimics that contain DPro in the i+1 position and a β-, γ-, or δ-amino acid in the i+2 position [21]. A peptide with a α,δ turn unit adopts a β-hairpin structure in solid state, while peptides with α,β and α,γ turn units adopt β-hairpin structures in methanol (Figure 2B).

β-Turn mimics that undergo a rapid light-triggered conformational change permit studying β-sheet folding processes. Previous studies showed that the cis isomer of an m, m′-substituted azobenzene amino acid induces a β-hairpin conformation in peptides, while the trans isomer disfavors this conformation (Figure 2D) [22,23]. The photo-induced cis-trans isomerization of the azo bond occurs efficiently in picoseconds. Moroder, Zinth, Renner, Tavan, and coworkers have monitored the photo-triggered folding-unfolding process of a peptide that contains this azobenzene turn unit by using ultrafast time-resolved mid-IR spectroscopy [24•]. Gogoll and coworkers have reported an m, m′-substituted stilbene derivative as an alternative to the photo-switchable azobenzene turn unit in linear and cyclic peptides [25]. The stilbene double bond suffers from a slow and incomplete cis-trans isomerization, but is more thermally stable than the azo bond. In linear peptides, both the cis and trans isomers of the stilbene derivative fail to induce β-hairpin structures in methanol and in DMSO. In cyclic peptides containing both the stilbene turn unit and a DPro-Gly turn unit, only the cis isomer supports β-sheet folding.

Several other research groups have reported new β-turn mimics that induce β-hairpin folding in peptides. Guan and Oh have developed a 1,4-disubstituted 1,2,3-triazole-based β-turn mimic that induces a β-hairpin-like structure for a small peptide in chloroform (Figure 2D) [26]. Silvani and coworkers have reported β-hairpin folding of small peptides containing a tetrahydroisoquinoline-based β-turn mimic in chloroform (Figure 2E) [27]. Piarulli and coworkers have developed a diketopiperazine amino acid that induces a β-hairpin conformation in peptide sequences in DMSO (Figure 2F) [28].

Chemical model systems are uniquely suited for studying parallel β-sheet folding, because small peptides composed only of α-amino acids cannot fold to form parallel β-sheets. β-Hairpin analogues containing diamine or diacid turn units provide good models with which to study parallel β-sheet folding, because they can orient peptide chains in parallel. Gellman and coworkers previously introduced the reverse-turn diamine linker DPro-DADME that aligns two C-terminally attached peptide strands in a parallel orientation in water (Figure 2G) [29]. The authors evaluated the folding thermodynamics of this model system by using a cyclic peptide as the benchmark for folding [30].

In their initial efforts to induce parallel β-sheet folding by diacid linkers, Gellman and coworkers employed succinyl-Gly as a turn unit. This diacid linker only partially further stabilizes the parallel β-sheet folding nucleated by the DPro-DADME diamine linker in the benchmark cyclic peptide described above [30]. Replacing the succinic acid with the more rigid S,R- or R,S-cis-cyclohexanedicarboxylic acid (CHDA), Gellman and coworkers have recently developed the CHDA-Gly turn unit as the first diacid linker that promotes parallel β-sheet folding in water (Figure 2H) [31•]. The CHDA-Gly diacid linker aligns two N-terminally attached peptide strands in a parallel orientation. Swapping the attached peptide strands eliminates folding by replacing favorable side-chain interactions with less favorable ones. This finding suggests that favorable side-chain interactions between parallel strands [32] are more important in folding than the reverse-turn linker or the intrinsic β-sheet propensity of the residues. The authors anticipate that combining the CHDA-Gly diacid linker and the DPro-DADME diamine linker may enable the preparation of both parallel cyclic peptides and multistranded parallel β-sheets.

Cyclic β-sheet peptides containing β-turn and β-strand mimics

Macrocyclization helps stabilize β-sheet structure in the naturally occurring peptide antibiotics gramicidin S and θ-defensin and has been used extensively to create well-folded β-sheet peptides [16•,20].

To help enforce β-sheet structure and reduce the dependence of folding on sequence, Nowick and coworkers have developed macrocyclic peptides containing β-strand and β-turn mimics [33,34,35••,36]. One class of these macrocyclic β-sheet peptides consists of a pentapeptide strand, a Hao β-strand mimic, and two δ-linked ornithine (δOrn) β-turn mimics in a 42-membered ring (Figure 3A) [33,34,36]. Many of the 42-membered-ring macrocyclic peptides adopt folded β-sheet structures in water. Nowick and coworkers are now using these peptides as ligands to bind protein β-sheets and control protein-protein interactions. In addition to imparting water solubility, the δOrn α-amino group allows preparation of bivalent structures in which a linker connects two molecules (Figure 3B). A related class of macrocyclic β-sheet peptides is described in the next section (Figure 3C)[33,35••,36].

Figure 3.

Figure 3

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Cyclic β-sheet peptides containing β-strand and β-turn mimics. (A) 42-Membered-ring cyclic β-sheets containing Hao and δOrn units. (B) Bivalent structure based on 42-membered-ring cyclic β-sheets. (C) 54-Membered-ring cyclic β-sheets containing Hao and δOrn units.

Mimicry of β-sheet quaternary structure through non-covalent interactions

Artificial β-sheets that participate in intermolecular β-sheet interactions provide easy-to-study chemical models of the interactions that occur in complex protein assemblies and aggregates.

Nowick and coworkers previously developed chemical models that form antiparallel β-sheet dimers in non-hydrogen-bonding solvents [33,36]. Chemical models that form well-defined β-sheet dimers in water proved more challenging. Hydrogen bonding between water molecules and the amide groups of small peptides strongly competes with the hydrogen bonding associated with intermolecular β-sheet interactions. In addition, hydrophobic interactions in β-sheets can result in non-specific aggregation. Nowick and coworkers have developed 54-membered-ring cyclic peptides that mimic β-sheet quaternary structure in water through intermolecular antiparallel β-sheet interactions (Figures 3C and 4A) [33,35••,36]. These artificial β-sheets consist of a heptapeptide strand, two Hao β-strand mimics, and two δOrn turn β-mimics. Many of these peptides form a tetrameric β-sheet sandwich, which is in equilibrium with a partially folded monomer. In the tetrameric β-sheet sandwich, two edge-to-edge β-sheet dimers further dimerize through stabilizing hydrophobic interactions. Variations in the heptapeptide sequence reveal the importance of hydrophobic interactions in tetramer formation. The authors are currently exploring the interactions of this system with protein β-sheets and β-sheet aggregates.

Figure 4.

Figure 4

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Chemical models of β-sheet quaternary structure. (A) Edge-to-edge antiparallel β-sheet dimer present in the tetrameric β-sheet sandwich of 54-membered-ring cyclic β-sheet peptides containing Hao and δOrn units. (B) Parallel β-sheet dimer containing succinic or fumaric diacid linkers and β-strand and β-turn mimics. (C) Antiparallel β-sheet-like dimer of Ach-based cyclic α,γ-peptides. (D) Antiparallel β-sheet dimer stabilized by a disulfide linkage. (E) Antiparallel β-sheet heterodimer stabilized by metal coordination.

Parallel β-sheet interactions are especially important in peptide and protein aggregation, such as β-amyloid peptide aggregation in Alzheimer’s disease. To study intermolecular parallel β-sheet interactions, Nowick and Levin have recently developed artificial β-sheets that dimerize through parallel β-sheet interactions in chloroform (Figure 4B) [36,37•]. In these β-sheets, two peptide strands are N-terminally linked with a succinic or fumaric diacid linker. An (S)-2-aminoadipic acid β-turn mimic connects the resulting linked dipeptide strand to a β-strand mimic. In the dimer, one edge of the linked dipeptide strand is blocked through intramolecular antiparallel β-sheet hydrogen bonding with the β-strand mimic, while the other edge participates in intermolecular parallel β-sheet interactions. The authors anticipate using this new model system to study side-chain interactions in parallel β-sheet systems and extending this model system to aqueous solutions.

Spontaneous stacking of certain cyclic peptides through intermolecular β-sheet-like hydrogen bonding produces nanotubes. Previously reported nanotube-forming cyclic peptides include cyclic peptides with α-amino acids of alternating chirality and cyclic β-peptides [38,39]. Selective N-methylation on one edge limits the stacking of cyclic peptides to dimer formation. Granja and coworkers have recently developed new nanotube-forming cyclic peptides composed of alternating α-amino acids and cyclic γ-amino acids with alternating chirality. Cyclic α,γ-peptides with cyclic γ-cis-amino acids, such as cis-3-aminocyclopentanecarboxylic acid (Acp) and cis-3-aminocyclohexanecarboxylic acid (Ach), form tubular structures in non-hydrogen-bonding solvents and in the solid state. N-Methylation of either the α-amino acids or cyclic γ-amino acids affords antiparallel β-sheet-like dimers (Figure 4C), with N-methylation of the cyclic γ-amino acids providing higher dimerization constants [40,41]. Heterodimerization occurs preferentially between Acp- and Ach-based cyclic peptides, and fluorescence studies of peptides bearing different chromophores allow analysis of the heterodimer-homodimer equilibrium [42,43].

Kimura and coworkers have reported parallel β-sheet stacking of cyclic β-peptides based on trans-2-aminocyclohexanecarboxylic acid and trans-pyranoid sugar amino acids in the solid state [44,45,46]; Chandrasekhar and coworkers have reported parallel β-sheet stacking of cyclic β-peptides based on cis-furanoid sugar amino acids in the solid state and in non-hydrogen-bonding solvents [47].

Many enzymes, binding proteins, and membrane pores contain β-barrel structures consisting of a tubular β-sheet comprising β-strand “staves”. In the late 1990s, Matile and coworkers introduced a class of chemical models of β-barrels comprising octaphenyl templates bearing peptide strands, which self-assemble to form tubular tetrameric structures [48]. In these structures, the octaphenyl templates act as staves and the peptide strands interdigitate to form β-sheet “hoops”. The biphenyl torsions in the octaphenyl staves create angles in the attached β-sheets and prevent aggregation, while intermolecular antiparallel β-sheet interactions stabilize the tetrameric β-barrel-like structure. Matile and coworkers have used variants of artificial β-barrels as receptors, ion channels, pores, catalysts, and sensors. The authors have recently developed a muticomponent-sensing system that combines signal-generating enzymes, signal-transducing artificial β-barrels, and signal-amplifying reactive pore-blockers [49]. This artificial tongue selectively responds to several sweet-, sour-, and umami-tasting molecules. Matile and coworkers have summarized the development and application of these artificial β-barrels in two recent reviews [50,51].

Mimicry of β-Sheet quaternary structures through covalent bonds

Many protein quaternary structures are stabilized through additional linking of protein domains by disulfide bond formation or metal coordination. Artificial β-sheets with these types of covalent or coordinative bonds provide another type of easy-to-study chemical model of the interactions that occur in complex protein assemblies and aggregates.

Disulfide bond formation among cysteine residues to form cystine occurs widely in protein quaternary structure. Linton and Cashman have demonstrated that disulfide bond formation induces β-sheet hydrogen bonding between the attached peptide strands in non-hydrogen-bonding organic solvents [52•]. A cystine dimer of a tripeptide with a central cysteine residue forms a small antiparallel β-sheet structure (Figure 4D). This result shows that a disulfide bond between a non-hydrogen-bonded cysteine pair not only acts as a linkage between β-strands, but also further stabilizes the β-sheet structure. Subsequent studies of a β-hairpin peptide model system containing cystine by Rico, Jiménez, and coworkers corroborate the stabilization of β-sheet structure by disulfide linkages between non-hydrogen-bonded cysteine pairs [53•].

Metal coordination also occurs widely in protein quaternary structure, with the protein imidazole, thiol, and carboxylate functionalities acting as metal-coordinating ligands. Breit and coworkers are creating bidentate ligands in which intermolecular hydrogen bonding brings together two monodentate ligands. The authors initially obtained homodimeric helical structures by coordinating dipeptides bearing N-terminal phosphine groups to Pt(II) or Rh(I) in chloroform [54]. The authors have subsequently obtained heterodimeric β-sheet structures by coordinating a dipeptide bearing an N-terminal phosphine group and a complementary dipeptide bearing a C-terminal phosphine group (Figure 4E) [55•]. Size complementarity of the side chains (e.g. Val and Ala), heterochirality of the peptides (e.g. LVal and DVal), and peptide length favor the heterodimeric β-sheet structures over the competing homodimeric helical structures.

Conclusion

Chemical models of β-sheet structures increase the understanding of forces involved in protein β-sheet folding and intermolecular β-sheet interactions. Unnatural templates, such as β-strand mimics, β-turn mimics, and various linkers help induce and stabilize β-sheet folding or enforce intermolecular β-sheet interactions in small artificial β-sheets. These unnatural templates furthermore help control aggregation and impart properties, such as modularity, solubility, and parallel alignment, which may be difficult to achieve with natural peptides and proteins. Within the past two decades, many chemical model systems have been developed to study β-sheet folding. A new trend focuses on chemical model systems that demonstrate intermolecular β-sheet interactions. Another trend focuses on chemical model systems that exhibit parallel β-sheet structures and interactions. The findings from these studies will help researchers better control or modify β-sheet interactions and may have profound implications for the treatment of Alzheimer’s and other neurodegenerative diseases.

Acknowledgments

The authors thank the National Institutes of Health and the National Science Foundation for grant support (GM-49076, CHE-0750523).

Footnotes

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