The sophisticated chemical functions carried out by the proteins nearly always require a specific tertiary fold, presumably because it is only at the level of tertiary structure that there is enough structural variation to allow wide latitude in the arrangement of the functional groups that constitute the active site. The remarkable range of chemical capabilities that evolution has elicited from proteins suggests that it might be possible to design analogous capabilities into unnatural polymers that fold into compact and specific conformations. A fundamental challenge in the design of synthetic polypeptides that folds in defined ways is the generation of a sequence of monomer buildings blocks that will manifest the correct fold. In this work, I will focus upon the properties of gramicidin A analogues with the aim to design and synthesize complex channel-forming heteropolymeric structures which may reveal novel structural and functional properties not observed in nature. Several studies have indicated that the ion-conducting transmembrane channels formed by gramicidin A in lipid bilayer originated through a dimerization process, and Urry [1] has proposed that the channels are helical dimers consisting of two single stranded ?-helices connected head-to-head (formyl-end-to-formyl-end). These helices should be ?6.3-helices (the superscript indicates the approximate number of residues per turn) but also ?4.4-helices, ?8.2- helices, and ?9.0-helices have been considered. Urry's proposal is consistent with a number of experimental observations, and the ability of single- and double-stranded ?-helices to give head-to-head dimers has been demonstrated either with gramicidin A [1,2] as with synthetic N-formyl oligopeptides[3-5]. Systematic studies on the novo design of ?-spiral using the 20 naturally occurring ?-amino acids have resulted in the formulation of a set of rules for the construction of stable helices [6]. On these bases here, we report the results of a study on the tendency to polymerization of 'models' peptides with large propensity to assume helical structures. We have synthetized and observed heteropeptides (i.e. composed of two or more types of monomer) with different length and compositions that, after polymerization, can assume tubular structure. Conformational analysis of this oligopeptides provides important information about polymerization method, balance between hydrogen bonds and hydrophobic interactions, modulation of number of residues per turn of helix, insertion of functionalized residues without alter the stability of backbone structure, that will be here discussed, References [1] Urry D.W, Proc.Natl. Acad. Science U.S.A. (1983) 68, 672 [2] Benoit Roux, Acc. Chem. Res. (2002) 35, 366-375 [3]Lorenzi G.P., Muri-Valle V., Bangerter F., Helv.Chim. Acta (1984) 67, 1588-1592, [4] Lorenzi G.P., Jackle H., Tomasic L., Rizzo V., Pedone C., J. Am. Chem. Soc. (1982) 104, 1728-33 [5] Fenude Schoch E., Römer U.D., Lorenzi G.P., Int. J. Peptide Protein Res.(1994) 44, 10-18 [6] Urry D.W., Phil. Trans. R. Soc. Lond. B (2002) 357, 169-184 [7] Navarro E., Fenude E., Celda B., Biopolymers (2001) 59, 110-117
Polymerization of Structural Elements lead to Tubular Biopolymers
E Fenude;M Saviano
2016
Abstract
The sophisticated chemical functions carried out by the proteins nearly always require a specific tertiary fold, presumably because it is only at the level of tertiary structure that there is enough structural variation to allow wide latitude in the arrangement of the functional groups that constitute the active site. The remarkable range of chemical capabilities that evolution has elicited from proteins suggests that it might be possible to design analogous capabilities into unnatural polymers that fold into compact and specific conformations. A fundamental challenge in the design of synthetic polypeptides that folds in defined ways is the generation of a sequence of monomer buildings blocks that will manifest the correct fold. In this work, I will focus upon the properties of gramicidin A analogues with the aim to design and synthesize complex channel-forming heteropolymeric structures which may reveal novel structural and functional properties not observed in nature. Several studies have indicated that the ion-conducting transmembrane channels formed by gramicidin A in lipid bilayer originated through a dimerization process, and Urry [1] has proposed that the channels are helical dimers consisting of two single stranded ?-helices connected head-to-head (formyl-end-to-formyl-end). These helices should be ?6.3-helices (the superscript indicates the approximate number of residues per turn) but also ?4.4-helices, ?8.2- helices, and ?9.0-helices have been considered. Urry's proposal is consistent with a number of experimental observations, and the ability of single- and double-stranded ?-helices to give head-to-head dimers has been demonstrated either with gramicidin A [1,2] as with synthetic N-formyl oligopeptides[3-5]. Systematic studies on the novo design of ?-spiral using the 20 naturally occurring ?-amino acids have resulted in the formulation of a set of rules for the construction of stable helices [6]. On these bases here, we report the results of a study on the tendency to polymerization of 'models' peptides with large propensity to assume helical structures. We have synthetized and observed heteropeptides (i.e. composed of two or more types of monomer) with different length and compositions that, after polymerization, can assume tubular structure. Conformational analysis of this oligopeptides provides important information about polymerization method, balance between hydrogen bonds and hydrophobic interactions, modulation of number of residues per turn of helix, insertion of functionalized residues without alter the stability of backbone structure, that will be here discussed, References [1] Urry D.W, Proc.Natl. Acad. Science U.S.A. (1983) 68, 672 [2] Benoit Roux, Acc. Chem. Res. (2002) 35, 366-375 [3]Lorenzi G.P., Muri-Valle V., Bangerter F., Helv.Chim. Acta (1984) 67, 1588-1592, [4] Lorenzi G.P., Jackle H., Tomasic L., Rizzo V., Pedone C., J. Am. Chem. Soc. (1982) 104, 1728-33 [5] Fenude Schoch E., Römer U.D., Lorenzi G.P., Int. J. Peptide Protein Res.(1994) 44, 10-18 [6] Urry D.W., Phil. Trans. R. Soc. Lond. B (2002) 357, 169-184 [7] Navarro E., Fenude E., Celda B., Biopolymers (2001) 59, 110-117I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
