Helix–helix interconversion rates of short ¹³C‐labeled helical peptides as measured by dynamic NMR spectroscopy

Abstract

The rates at which a peptide hexamer and a peptide octamer interconvert between left- and right-handed helical forms in CD2Cl2 solution have been characterized by 13C dynamic NMR (DNMR) spectroscopy. The peptide esters studied are Fmoc-(Aib)n-OtBu (n = 6 and 8), where Fmoc is 9-fluorenylmethyoxycarbonyl and Aib is the strongly helix-forming residue alpha-aminoisobutyric acid. Because the Aib residue is itself achiral, homooligomers of this residue form a 50/50 mixture of enantiomeric 3(10)-helices in solution. It has been demonstrated (R.-P. Hummel, C. Toniolo, and G. Jung, Angewandte Chemie International Edition, 1987, Vol. 26, pp. 1150-1152) that oligomers of Aib interconvert on the millisecond timescale. We have performed lineshape analysis of 13C-NMR spectra collected for our peptides enriched with 13C at a single residue. Rate constants for the octamer range from 6 s(-1) at 196 K to about 56,500 s(-1) at 320 K. At all temperatures, the hexamer interconverts about three times faster than the octamer. Eyring plots of the data reveal experimentally indistinguishable DeltaH++ values for the hexamer and octamer of 37.8 +/- 0.6 and 37.6 +/- 0.4 kJ mol(-1) respectively. The difference in the rates of interconversion is dictated by entropic factors. The hexamer and octamer exhibit negative DeltaS++ values of -29.0(-1) +/- 2.5 and -37.3 +/- 1.7 J K(-1) mol(-1), respectively. A mechanism for the helix-helix interconversion is proposed. and calculated DeltaG++ values are compared to the estimate for a decamer undergoing a helix-helix interconversion.

Aggregation propensity of Aib homo‐peptides of different length: an insight from molecular dynamics simulations

“…Furthermore, combining the results obtained from simulations with only one (Figures and ) and with six replicas of the peptide (Figure ), we can reasonably predict that under these conditions transitions between P‐ and M‐helices take place in the timescale of tens of nanosecond. Notably, helix screw‐sense reversal is usually considered a two‐state process . However, in our simulations, intermediates with different conformations are significantly populated, often promoted by the initial change of the ψ torsion angle.…”

Antiamoebin I in Methanol Solution: Rapid Exchange between Right‐Handed and Left‐Handed 310‐Helical Conformations

“…Analogous fast (on the NMR time scale) conformational transitions between enantiomeric 3 10 -helices have been early reported for poly-Aib peptides (hexamer, octamer, and decamer) [41] [50]. These transitions are highly cooperative, very rapid (ca.…”

Acceleration of Short Helical Peptide Conformational Dynamics by Trifluoroethanol in an Organic Solvent

“…[16] In our system, the interconversion of helix handedness requires no amide-bond isomerization but it does require the breaking and reforming of all six intramolecular hydrogen bonds. In a previous work, [17] we presented evidence for a helix/helix-interconversion mechanism in which peptides "zipper" from one form of handedness to another, breaking and then reforming a very small number of intramolecular hydrogen bonds at a time. A plausible mechanism for the zippering between left-and right-handed helices would involve successive "flips" of the peptide-bond unit and concerted rotations of y i and f i+1 .…”

“…Interconversion of the helix handedness changes the magnetic environment of the b-carbons, which broadens the NMR resonance ( Figure 1). [14,17] Assuming a fully cooperative, twostate mechanism, the rate of chemical exchange for the two methyl groups indicates the rate of helix/ helix interconversion. Note that we are not characterizing helix!random coil kinetics, rather a conformational change between two well-defined helical states.…”

“…Qualitatively, however, the Eyring plots suggest that the kinetics in 5 % TFE solution will have the lowest, most negative DS°, whereas the 10 and 30 % solutions will have less negative DS°values than neat CH 2 Cl 2 . The DS°f or the octamer in neat CH 2 Cl 2 has been previously measured as À37 J K À1 mol À1 over a temperature range of 200 K to 315 K. [17] It is possible that at low TFE concentrations, the ordering of TFE solvent around an exposed amide in the transition state leads to a more negative value of DS°. However, increasing concentrations of TFE could broaden the peptide's transition state ensemble for interconversion, eventually making DS°less negative than in neat CH 2 Cl 2 .…”