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Proline cis-​trans isomerization and its implications for the dimerization of analogues of cyclopeptide stylostatin 1: a combined computational and experimental study
Lopez-Martinez, C.; Flores-Morales, P.; Cruz, M.; Gonzalez, Teresa; Feliz Rodenas, Miguel; Diez Pascual, Anna; Campanera Alsina, Josep Maria
Universitat de Barcelona
Cis and trans proline conformers are often associated with dramatic changes in the biological function of peptides. A slow equilibrium between cis and trans Ile-Pro amide bond conformers occurs in constrained derivatives of the native marine cyclic heptapeptide stylostatin 1 (cyclo-(NSLAIPF)), a potential anticancer agent. In this work, four cyclopeptides, cyclo-(NSTAIPF), cyclo-(KSTAIPF), cyclo-(RSTAIPF) and cyclo-(DSTAIPF), which are structurally related to stylostatin 1, are experimentally and computationally examined in order to assess the effect of residue mutations on the cis-trans conformational ratio and the apparent capacity to form dimeric aggregates. Primarily, cyclo-(KSTAIPF) and cyclo-(RSTAIPF) showed specific trends in circular dichroism, MALDI-TOF and HPLC purification experiments, which suggests the occurrence of peptide dimerization. Meanwhile, the NMR spectrum of cyclo-(KSTAIPF) indicates that this cyclopeptide exists in the two slow-exchange families of conformations mentioned above. Molecular dynamics simulations combined with quantum mechanical calculations have shed light on the factors governing the cis/trans conformational ratio. In particular, we have found that residue mutations affect the internal hydrogen bond pattern which ultimately tunes the cis/trans conformational ratio and that only trans conformers are capable of aggregating due to the shape complementarity of the two subunits.
Química orgànica
Pèptids
Organic chemistry
Peptides
(c) Lopez-Martinez, C. et al., 2016
info:eu-repo/semantics/embargoedAccess
Artículo
info:eu-repo/semantics/acceptedVersion
Royal Society of Chemistry
         

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