Conformation of Boc‐L‐Ala‐Aib‐L‐Ala‐OMe in the Crystal and in Solution

Abstract

Boc-L-Ala-Aib-L-Ala-OMe (1) crystallizes in the space group P2, with a = 11.732(1), b = 6.013(1), c = 14.195(2) A, 0 = 91.76(1)', and Z = 2 ( R value for 3089 reflexions: 0.047). The peptide adopts a new type of B-turn with a very wide 4 + 1 hydrogen bond distance of 3.621 A. As for Ac-r-Ala-Aib-L-Ala-Me this distortion can be attributed to strong intermolecular hydrogen bonds forming a two-dimensional network in the bc plane. Temperature and solvent dependent 'H and I3C NMR reveal a hydrogen bond from Boc-CO to NH-3Ala in solution, E / Z isomerism of the Boc urethane bond, and a large magnetic nonequivalence of the two geminal Aib methyl groups. The unusual conformation of 1 is reflected also in its CD spectrum, which differs from most of comparable Aib containing tripeptides. Konformation von Boc-L-Ala-Aib-I.-Ala-OMe im Kristall und in LosungRoc-L-Ala-Aib-L-Ala-OMe (1) kristallisert in der Raumgruppe P2, mit a = 11.732(1), b = 6.013(1), c = 14.195(2) A, P = 91.76(1)' und Z = 2 (R-Faktor fur 3089 Reflexe: 0.047). Das Peptid bildet einen neuen Typ eines P-Turns mit einer sehr langen 4 -+ 1-Wasserstoffbrucke (3.621 A).Diese Aufweitung laOt sich wie bei Ac-~-Ala-Aib-~-Ala-OMe mi: der Ausbildung eines zweidimensionalen Netzes von starken intermolekularen Wasserstoffbrucken in der bc-Ebene erklaren. Temperatur-und L~sungsmittel-abhangige 'H-und 13C-NMR zeigen eine Wasserstoffbriicke von Boc-CO zu NH -'Ala in Lbsung, E/Z-Isomerie der Boc-Urethanbindung und eine grol3e magnetische Nichtaquivalenz der beiden geminalen Aib-Methylgruppen. Die ungewohnliche Konformation von 1 spiegelt sich auch im CD-Spektrum wider, das sich von den meisten Aib-Tripeptiden unterscheidet.The particular role of a-aminoisobutyryl residues for the restriction of conformational mobility of peptide backbones has been discussed mainly in this journal in context with the following almost complete oligopeptide series of X-ray structures: Boc-Aib-OH 'I, Boc-L-Ala-Aib-OH", Boc-Gly-L-Ala-Aib-OMe", Ac-L-Ala-Aib-~-Ala-OMe~), BocAib-~-Ala-Aib-L-Ala-Aib-OMe~.~', and the a-helical Boc-L-Ala-Aib-L-Ala-Aib-L-Ala-~-Glu(OBzl)-L-Ala-Aib-L-Ala-Aib-L-Ala-OMe~~~'. We refer also t o the literature of other groups working i n this field, which is cited in o u r previous papers'-9). Interest in the conformation of 2-methylalanyl residues-containing peptides steadily increases as shown on publications, which appeared recently" 'j).The present study o n the tripeptide Boc-L-Ala-Aib-L-Ala-OMe (1) was undertaken in order t o clarify the following: Is the new type of an unusually widened and flat 0-turn 0 Verlag

The Propensity of α‐Aminoisobutyric Acid (=2‐Methylalanine; Aib) to Induce Helical Secondary Structure in an α‐Heptapeptide: A Computational Study

“…Though a survey of a large set of helical structures does not give a clear correlation between the Aib content of a peptide and the deviation of its helical structure from the canonical helical secondary structure, we can not rule out the possibility that the formation of the helix actually results from the combined effect of all Aib residues in an Aib-rich peptide. For tripeptides with a single Aib residue, helical structure is still observed [19] [20], while there is no conclusive evidence that the helical folding in the presence of Aib residues is chain-lengthindependent. Meanwhile, for short peptides, the secondary structure observed in X-raycrystallographic studies is not necessarily representative for the conformation of the peptide in solution due to the large difference between the two environments.…”

Conformational studies of Aib‐rich peptides containing lactam‐bridged side chains: Evidence of 310‐helix formation

“…This is shown by Cβ‐selective HMQC experiments (Figure 4). A difference in 13 C chemical shifts of the two pro‐chiral methyl groups of 2 ppm or higher has been ascribed to the presence of a stable helical conformation in solution 26–28. The Δδ values of the three peptides, determined by Cβ‐selective HMQC experiments are reported in Table I.…”

Solution conformation of tripeptides by NMR spectroscopy and force-field calculations

“…The 3JNH,c~, a coupling constants vary around 6.5 Hz, indicating hereby the existence of a random coil [6][7][8][9]. In 3 also new signals were obtained when changing CDCI 3 to DMSO-d6 (cis/trans isomers).…”

“…The corresponding temperature coefficients of the NH protons in 1 (Ala ~ 5.22 ppb/K; Val z 4.72 ppb/K; Val 3 5.73 ppb/K) and 3 (Ala 5.73 ppb/ K; Val 4.47 ppb/K) in CDCI 3 are rather large and the NH protons proved hereby not to be involved in intramolecular hydrogen bonding [6][7][8][9]; in DMSO-d6 the temperature coefficients are even slightly larger. Only in 2, the temperature coefficient of the strictly linear dependences for Ala I (2.36 ppb/K) is significantly smaller and proved the NH proton to participate in intramolecular hydrogen bonding; the corresponding value for Val in 2 is not significant (3.64 ppb/K) [6][7][8][9]. In DMSO-d6 the temperature coefficients change to larger values; intermolecular hydrogen bonding to the solvent in competition with the intramolecular analogue, obviously, is the reason for this.…”