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Self-organizing systems - Foldamers*
The principles of protein design are not restricted to the realm of the heteropolymers of α-amino acids, but can be generalized and extended to any polymer with a tendency to fold into the periodic and/or specific compact structures referred to as foldamers.1,2 Such foldamers include synthetic oligomers constructed from β-amino acids as monomers, designated β-peptides, which are among the most thoroughly studied models in foldamer chemistry, and have acquired considerable importance.3,4
For the biopolymer community, there are a number of reasons for the synthesis of β-amino acid-containing analogs and analysis of their structures. With respect to foldamer design, β-peptides are close relatives of α-peptides. Their amide bonds also allow the formation of stabilizing H-bonds. β-amino acids are homologues of α-amino acids, where the amide groups in the β-peptide backbone are separated by two carbon atoms. This provides new options regarding the substituent pattern and the spatiality on C2 and C3 backbone atoms and controlling the secondary structure. A noteworthy example of the conformationally constrained systems is the family of cyclic β-amino acids, where control of the torsion Θ is achieved by inclusion of C2 and C3 into a cyclic structure.5-7 For these β residues, the antiperiplanar arrangement is inaccessible, and the folded structures with helical symmetry are therefore promoted.
The β-peptide foldamers have a number of interesting structural features. The H-bonds stabilizing the periodic conformations can attain parallel or antiparallel orientations with respect to the directionality of the β-peptide chain. The orientation of the H-bonds is closely connected to the number of atoms comprising the H-bonded ring formed between the donor and acceptor atoms. For the structures with 6-, 10- and 14-membered rings, the donor to acceptor orientation is parallel to the chain directionality, going from the N-terminal to the C-terminal, while in the 8- and 12-helices and in the 8-strand the orientation is antiparallel. Besides the novel H-bonding patterns, the sense of the helical twist can also vary, leading to right-handed or left-handed helices. Figure 1 depicts only the conformations with left-handed helicity. The secondary structures can be rationally designed with cyclic β-residues and stereochemical patterning in the backbone. Through the local torsion effects along the backbone the secondary structure can be programmed.8
Figure 1
For β-peptides, not only the controlled secondary structures attract interest, but the self-assembly of the secondary structure units into tertiary structure motifs is an extremely important aspect too. The amphipatic helices having engineered hydrophobic and hydrophilic faces show helix-bundle formation.9 Hydrophobic helices made of cyclic β-amino acid residues with various chain-lengths also exhibit significant self-association in polar solvents (Figure 2).10
Figure 2
The strong structure inducing effect of the cyclic β-amino acids can readily be utilized in the 3D-QSAR studies of flexible peptide ligands. The incorporation of the various β-amino acid diastereomers results in conformationally diverse compounds showing variations of several magnitudes in the biological activity. The newly developed 3+3D-QSAR method is capable of exploiting this information, and finally provides a ligand based prediction for the active conformation (Figure 3).11
Figure 3
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* Prepared with the generous help of Drs. Tamás Martinek and Ferenc Fülöp.
(1) Goodman, C. M.; Choi, S.; Shandler, S.; DeGrado, W. F. Nat. Chem. Biol. 2007, 3, 252 – 262.
(2) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173.
(3) Hayen A.; Schmitt M. A.; Ngassa F. N.; Thomasson K. A.; Gellman S. H. Angew. Chem. Int. Ed. 2004, 43, 505 –510.
(4) (a) Gademan K.; Hane, A.; Rueping M.; Jaun B.; Seebach D. Angew. Chem. Int. Ed. Engl. 2003, 42, 1534-7; (b) Fülöp, F.; Martinek, T. A.; Tóth, G. K. Chem. Soc. Rev. 2006, 35, 323 – 334.
(5) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem. Rev. 2001, 101, 3219.
(6) Appella, D. H.; Christianson, L. A.; Karle, I. L.; Powell, D. R.; Gellman, S. H. J. Am. Chem. Soc. 1996, 118, 13071.
(7) (a) Martinek, T. A.; Tóth, G.; Vass, E.; Hollósi, M.; Fülöp, F. Angew. Chem. Int. Ed. 2002, 41, 1718. (b) Martinek, T.A.; Fülöp, F. Eur. J. Biochem. 2003, 270, 3657.
(8) Mándity, M. I.; Wéber, E.; Martinek, T. A.; Olajos. G.; Tóth, G. K.; Vass, E.; Fülöp, F. Angew. Chem. Int. Ed. 2009, 48, 2171 – 2175.
(9) (a) Appella, D. H.; Christianson, L. A.; Karle, I. L.; Powell, D. R.; Gellman, S. H. J. Am. Chem. Soc. 1999, 121, 6206-6212. (b) Raguse, T. L.; Lai, J. R.; LePlae, P. R.; Gellman, S. H. Org. Lett. 2001, 3, 3963-3966.
(10) (a) Hetényi, A.; Mándity, I.M.; Martinek, T.A.; Tóth, G.K.; Fülöp, F. J. Am. Chem. Soc. 2005, 127, 547-553; (b) Martinek, T. A.; Hetényi, A.; Fülöp, L.; Mándity, I. M.; Tóth, G. K.; Dékány, I.; Fülöp, F. Angew. Chem. Int. Ed. 2006, 45, 2396 – 2400.
(11) Martinek, T.A.; Ötvös, F.; Dervarics, M.; Tóth, G.; Fülöp, F. J. Med. Chem. 2005, 48, 3239-3250.
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