U. Link et al., CONFORMATIONS AND CONFORMATIONAL INTERCONVERSIONS OF DIASTEREOMERIC CYCLIC TETRAPROLINES, International journal of peptide & protein research, 42(5), 1993, pp. 475-483
Cyclic tetrapeptides exclusively composed of L- and D-Pro have been st
udied by theoretical means (conformational searches and molecular mech
anics calculations using the CHARMM program) supported by H-1-NMR spec
troscopy, X-ray analysis and chiroptical measurements. We explored the
entire conformational space of the diastereomers cyclo(LLLL-PrO4) (1)
, cyclo(LDLD-Pro4) (11) and cyclo(LLDD-PrO4) (III) including the low-e
nergy conformations and the related interconversion paths. The conform
ational interconversions were found to be restricted to cis/trans isom
erisations of the amide bonds. Owing to the polycyclic nature of cyclo
(PrO4) most of the cis/trans transitions are hindered by energy barrie
rs higher than 30 kcal/mol (up to 150-200 kcal/mol). A few transitions
are characterized by computed energy barriers comparable to those fou
nd in linear -Xxx-Pro- sequences (approximately 18 kcal/mol), and are
therefore experimentally significant. Experimental evidence has been o
btained in the case of cyclo(LDLD-PrO4), where two enantiomers are int
erconverted by a series of 4 cis/trans isomerisations ctct --> cttt --
> tttt --> tctt --> tctc. The Eyring activation parameters of this rea
ction were determined in H2O and in DMF by chiroptical measurements (D
ELTAH(not-equal) = 44 and 28 kcal mol; DELTAS(not-equal) = 59 and 22 c
al K-1 mol-1, respectively), and correlated with the calculated barrie
rs. In I and III comparable series of four cis/trans isomerisations re
late two main conformations with the peptide bond sequences ctct and t
ctc. In compound I pseudorotational images are interconverted via ctct
--> ccct --> cctt --> cctc --> tctc. The pathway ctct --> ccct --> cc
cc --> cctc --> tctc that relates diastereomeric main conformations of
III involves exclusively low-energy intermediates; however, the trans
itions leading to the all-cis conformation are energetically unfavoura
ble, and the conformational space is divided in three insulated domain
s. (C) Munksgaard 1993.