No abstract

We have previously shown that methionine can be used as a “switchable” residue for the design of peptides with alternative secondary structure preferences in the aggregated state (J. Am. Chem. Soc. 1993, 115, 12609). Redox-induced secondary structure changes in the 18-residue peptide Ac-YLKAMLEAMAKLMAKLMA-NH2 result from conversion of lipophilic methionine (M) to hydrophilic methionine sulfoxide (M°), which transforms a peptide capable of adopting an amphiphilic α-helical conformation into a peptide capable of adopting an amphiphilic β-strand conformation. Here we present a detailed characterization of the third oxidation state of this peptide, in which the methionine residues are oxidized to the sulfone state. The sulfone form behaves similarly to the sulfoxide form, even though the sulfone group is somewhat less hydrophilic than the sulfoxide group. These results provide support for the concept that the conformational preferences of peptides and proteins are strongly dependent upon the linear ordering of hydrophilic and lipophilic residues (“amphiphilic order”).

Hydroxamic acids are metal-binding compounds used by micro-organisms and possess applications in medicine and industry. Hydroxamic acids favor two conformations, E and Z; metal binding is limited to the Z conformation. The Z conformation may be identifiable by NOE spectroscopy, but analysis is complicated by the potential for long-range coupling as well as for relayed NOEs due to conformational switching. In this report, we re-examine the reported conformational preference of N-methyl acetohydroxamic acid (NMHA) in D(2)O using NOE spectroscopy. We find that the favored conformation of NMHA in aqueous solution is the E conformation, contrary to an earlier report. NOE build-up curves are proposed as a valuable tool to probe conformational behavior in similar systems.

No abstract

Hydroxamic acids (HAs) perform tasks in medicine and industry that require bidentate metal binding. The two favored conformations of HAs are related by rotation around the C(=O)-N bond. The conformations are unequal in stability. Recently, we reported that the most stable conformation of a small secondary HA in water places the oxygen atoms anti to one another. The barrier to C-N bond rotation may therefore modulate metal binding by secondary HAs in aqueous media. We have now determined the activation barrier to C-N rotation from major to minor conformation of a small secondary HA in D2O to be 67.3 kJ/mol. The HA rotational barrier scales with solvent polarity, as is observed in amides, although the HA barrier is less than that of a comparable tertiary amide in aqueous solution. Successful design of new secondary HAs to perform specific tasks requires solid understanding of rules governing HA structural behavior. Results from this work provide a more complete foundation for HA design efforts.