Synthesis, conformational studies, and molecular dynamics calculations of two cyclic tetrapeptides with 17- and 18-membered rings.
Two cyclic tetrapeptides [Boc-cyclo(-Xxx-Pro-Asn-Lys-)OMe (Xxx = Asp or Glu)] were synthesized and investigated by NMR spectroscopy. They were designed in order to mimic the salt bridge found in physalaemin. Isomers of the urethane bond were observed in DMSO solution. The ROESY spectrum allowed the assignment of many signals of the minor isomer of both compounds. Conformational studies based on the temperature gradients of the NH chemical shifts, coupling constants, and ROEs revealed a similar conformation for the Asp analogue as proposed for physalaemin. A beta I turn with Pro and Asn in the corner positions was found for the major isomer. No hydrogen bonds were detected for the major isomer of the cyclic Glu analogue. Molecular dynamics calculations, using the NMR based initial structures, yielded sets of conformations in agreement with the experimental data. It is concluded that the salt bridge in physalaemin is best approximated by a lactam formed from the original amino acids.
Hölzemann
G
G
Medicinal Chemistry Department, E. Merck, Darmstadt, Federal Republic of Germany.
Pachler
K G
KG
Eberhart
B
B
Hölzel
H
H
Kraft
M
M
Barnickel
G
G
D000595:Amino Acid Sequence; D003500:Cyclization; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry*; D010803:Physalaemin / Q000737:chemistry; D011487:Protein Conformation; D013816:Thermodynamics
D009842:Oligopeptides; D010456:Peptides, Cyclic; C070749:butyloxycarbonyl-cyclo(glutamyl-prolyl-asparaginyl-lysyl) methyl ester; C070750:butyloxycarbonyl-cyclo(aspartyl-prolyl-asparaginyl-lysyl) methyl ester; D010803:Physalaemin