The a-helix-stabilizing effect of different amino acid residues at the helical termini of short peptides in aqueous solution has been determined. Several dodecapeptides containing alanine, asparagine, aspartate, glutamine, glutamate, and serine at the amino terminus and arginine, lysine, and alanine at the carboxyl terminus were synthesized, and the a-helical content of each peptide was measured by using circular dichroism spectroscopy. The trend in a-helix-inducing ability of these amino acids was found to be as follows: In an a-helix, NH donors of the first four residues and CO acceptors of the last four residues lack intrahelical hydrogenbond partners. Presta and Rose (19) hypothesized that a necessary condition for helix formation is the presence of residues flanking the helix termini that have side chains to supply hydrogen-bond partners for unpaired main-chain NH and CO groups. Richardson and Richardson (20), by surveying several proteins of known structures, showed that at the amino termini of helices, there is a preponderance of amino acids with side chains that could hydrogen-bond with the free NH groups of the helix. Gierasch and coworkers (21) have shown that side-chain-backbone hydrogen bonding, as proposed by Presta and Rose, may also stabilize helix formation in peptides. Site-directed mutagenesis studies involving the amino-terminal residues of a-helices in native proteins have shown the significance of such hydrogen bonding in protein stability (22,23).We decided to test the Presta and Rose hypothesis in a peptide designed to fold into an isolated a-helix (24). The rationale for the design is as follows. (i) We chose a short a-helical segment (12 residues) resembling most a-helices found in native proteins. Further, we expected the capping effects to be more prominent in a short peptide. (ii) We introduced a proline and a glycine, amino acids traditionally known to be helix breakers, at positions 2 and 11, respectively, to demarcate the helical ends (25). We also hoped that the presence of the helix breakers might enable the side chains of the end residues to turn around and hydrogen-bond with the free NH and CO groups at the helical termini. (iii) The presence of a glutamate at position 4 and a lysine at position 7 increases solubility of the peptide and may also stabilize the helix by salt bridge formation (14). (iv) The rest of the amino acids were chosen to be alanine, which has a high tendency to form a-helices (26). (v) The respective positively and negatively charged side chains of arginine at the carboxyl end and aspartate at the amino end are expected to interact favorably with the helical dipole and stabilize the a-helix (13). (vi) The negatively charged carboxyl group of Arg-12 is amidated to eliminate repulsive interactions -between itself and the negative pole of the helical dipole. (vii) The a amino group of residue 1 was not acylated to prevent such an amide carbonyl from hydrogen bonding with the free NH groups at the amino terminus. The sequences of our model peptide an...
In t h e dinucleoside monophosphates a n d their protected derivatives, t h e nomenclature [170,180] is intended to signify t h e presence of both isotopes a t one position a t phosphorus. (b) T h e phosphorus decoupled I7O NMR spectra of 7a a n d 7b gave both singlets a t 93.04 ppm (water, p H 6.1) [Gerlt, J. A., private communication].acetate-acetonitrile (95:5)] retention time = 24 min at 1.5 mL/min. The peak coincided with that of unlabeled (3'-5')UpA: UV (H20) ha, 259 nm.(R,)-['70,'80]Uridylyl(3'+5')adenosine Ammonium Salt (7b). Using the same reaction conditions as described for compound 7a and starting with 5b (1 15 mg, 0.09 mmol), we obtained colorless fluffy 7b (40 mg, 75%). UV and HPLC data were identical with those of the isomer 7a and (3'45')UpA. Enzymatic cleavage at 37 OC with spleen phosphoAbstract: A mechanistic theory explains the stereochemical preferences of dehydrogenases dependent on nicotinamide cofactors that interconvert alcohols and ketones. This theory is based on the principles of stereoelectronic control and assumes that
The sequence of the ribonuclease from the ancestor of swamp buffalo, river buffalo, and ox, corresponding approximately to Pachyporrux lutidem, an extinct ruminant known from the fossil record, has been reconstructed using the rule of 'maximum parsimony'. This protein and two sequences that may have been intermediates in the evolution of modern ribonuclease have been constructed in the laboratory by site-directed mutagenesis, and their properties examined.
A research program has applied the tools of synthetic organic chemistry to systematically modify the structure of DNA and RNA oligonucleotides to learn more about the chemical principles underlying their ability to store and transmit genetic information. Oligonucleotides (as opposed to nucleosides) have long been overlooked by synthetic organic chemists as targets for structural modification. Synthetic chemistry has now yielded oligonucleotides with 12 replicatable letters, modified backbones, and new insight into why Nature chose the oligonucleotide structures that she did.The "standard model" of nucleic acid structure dates back to 1953 and two classic papers by Watson and Crick.132 It has been little altered since. The model holds that the energy of binding of two complementdry DNA or RNA (oligonucleotide) strands arises from the stacking of the hydrophobic nucleobases, while the specificity of the association arises from base pairing following two simple rules ("A pairs with T, G pairs with C"). No other class of natural products has reactivity that obeys such simple rules. Nor is it obvious how one designs a class of chemical substances that does so much so simply. Despite this chemical conundrum, and the position of nucleic acids at the center of natural product chemistry, few organic chemists have chosen to apply their synthetic skills to explore reactivity at the level of the oligonucleotide. Much work had been done, of course, in making structurally modified analogs of nucleosides, both in industry and academia.3 But most organic chemists, attracted by the structural intricacies of secondary metabolites, have neglected oligonucleotides as targets for structural modification.Some 15 years ago we began a program to fill this gap, developing synthetic organic chemistry and organic structural theory as it applies to nucleic acids in their oligomeric form. This began with one of the first two total syntheses of a gene encoding a p r~t e i n ,~ and has continued with the development of structurally altered oligonucleotides. As in all organic chemistry that alters the structure of natural products, our goal has been to learn more about how DNA and RNA work. We focus here on chemistry that has modified the bases, the sugars, and the backbones of oligonucleotides.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.