Cis/trans conformational equilibrium across the N‐methylphenylalanine2‐ N‐methylphenylalanine3 peptide bond of arginine vasopressin analogs

Trzepałka, Emilia; Kowalczyk, Wioleta; Lammek, Bernard

doi:10.1111/j.1399-3011.2004.00103.x

Cited by 12 publications

(12 citation statements)

References 56 publications

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“…[55,124] A polar solvent, such as DMSO with a large dipolar moment (3.96 D), favours cis-isomers, while less polar solvents, such as water (1.85 D), induce more trans-character. [60] Similar computational [30,32,[47][48][49][50][51][52][53] and other experimental [17,30,47,48,50,51,54,[56][57][58][59] results have been reported, showing that N-methylation of the amide bond increase the cis/trans ratio. [60] Similar computational [30,32,[47][48][49][50][51][52][53] and other experimental [17,30,47,48,50,51,54,[56][57][58][59] results have been reported, showing that N-methylation of the amide bond increase the cis/trans ratio.…”

Section: Ts1 Ts2 B3lyp/6-311++g(dp)supporting

confidence: 67%

The effect of N-methylation of amino acids (Ac-X-OMe) on solubility and conformation: a DFT study

et al. 2015

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N-Methylation has a significant impact on improving the oral bioavailability, lipophilicity and aqueous solubility of peptide-based lead drug structures. The selected mono-amino acid derivatives Ac-X-OMe, where X = Gly, Val, Leu, Ile, Phe, Met, Cys, Ser, Asp and His as well as their corresponding N-methylated analogues were studied. The clog P values of all N-methylated peptides are greater than those of native compounds. Quantum chemical calculations were performed to estimate the aqueous solubility of these lipophilic compounds using density functional theory (DFT). To confirm the contribution of dispersion forces on quantum chemical data, the long-range corrected (LC) hybrid density functional (ωB97X-D) was also probed for some amino acid derivatives. The ωB97X functional gave similar results. Our results reveal that after mono N-methylation of the peptide backbone, ΔGsolv becomes more negative (more water soluble) while polarizability and dipole moment are also increased. Natural atomic charges derived by natural bond orbital (NBO) analysis of N, C, and O atoms involved in amide functional group become more positive/(less negative) after N-methylation. All N-methylated amino acids have higher EHOMO (less negative) in comparison with the amino acid analogues, and in all cases N-methylation decreases EHOMO-LUMO. The calculated amide cis/trans activation energies (EA) of all the N-methylated amino acid derivatives were lower than that of native species. N-methylation of these compounds leads to an increase in lipophilicity, aqueous solubility, polarization, dipole moment and lowering of the cis/trans amide energy barrier (EA).

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Section: Ts1 Ts2 B3lyp/6-311++g(dp)supporting

confidence: 67%

The effect of N-methylation of amino acids (Ac-X-OMe) on solubility and conformation: a DFT study

et al. 2015

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“…The most likely origin of this conformational heterogeneity is cis-trans isomerism around the peptide bond involving the N-methyl group at Leu-8; this has been observed previously in other N-methylated peptides (34,35). Two different preparations of N-Me-Leu-8 showed identical ratios of major to minor species.…”

Section: Nmr Spectroscopysupporting

confidence: 60%

Rapid Optimization of a Peptide Inhibitor of Malaria Parasite Invasion by Comprehensive N-Methyl Scanning

Harris

Casey

Coley

et al. 2009

Journal of Biological Chemistry

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Apical membrane antigen 1 (AMA1) of the malaria parasite Plasmodium falciparum has been implicated in the invasion of host erythrocytes and is an important vaccine candidate. We have previously described a 20-residue peptide, R1, that binds to AMA1 and subsequently blocks parasite invasion. Because this peptide appears to target a site critical for AMA1 function, it represents an important lead compound for anti-malarial drug development. However, the effectiveness of this peptide inhibitor was limited to a subset of parasite isolates, indicating a requirement for broader strain specificity. Furthermore, a barrier to the utility of any peptide as a potential therapeutic is its susceptibility to rapid proteolytic degradation. In this study, we sought to improve the proteolytic stability and AMA1 binding properties of the R1 peptide by systematic methylation of backbone amides (N-methylation). The inclusion of a single N-methyl group in the R1 peptide backbone dramatically increased AMA1 affinity, bioactivity, and proteolytic stability without introducing global structural alterations. In addition, N-methylation of multiple R1 residues further improved these properties. Therefore, we have shown that modifications to a biologically active peptide can dramatically enhance activity. This approach could be applied to many lead peptides or peptide therapeutics to simultaneously optimize a number of parameters.

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“…In turn, the three-dimensional (3D) structures of I and IV obtained using molecular dynamic with the simulated annealing (SA) algorithm on the basis of the NMR data in aqueous solution, 38 as in DMSO, do not create a C 7 -membered moiety with Gly 9 on the top of it. It has also been noticed that the tendency to form a -turn in Cys 6 -Gly 9 increases in aqueous solution, which is especially observed in IV.…”

Section: Resultsmentioning

confidence: 99%

“…The greatest population -CO 7 distance within 2.5 Å , which indicates appropriate hydrogen bonds. Conformational investigations of the analogues in aqueous solution 9,38 revealed rather a -turn over Gly 9 than an inverseturn at position 8.…”

Section: Analysis Of the Calculated Structuresmentioning

confidence: 95%

Conformational studies of vasopressin analogues modified with N‐methylphenylalanine enantiomers in dimethyl sulfoxide solution

2006

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The conformations of [Arg8]vasopressin (AVP) analogues substituted at positions 2 and 3 with N-methylphenylalanine (MePhe) enantiomers were earlier investigated by using nuclear magnetic resonance (NMR) spectroscopy in aqueous solution. A comparison of the results obtained in H2O/D2O (9:1) and DMSO-d6 has shown the structures in the first solution to be more flexible than those in DMSO-d6. This is manifested by a higher percentage of minor conformations in H2O/D2O. The largest differences between the NMR spectra in both solvents were noticed for [MePhe2, D-MePhe3]AVP (II) and [D-Cys1,MePhe2,D-MePhe3]AVP (III). Namely, in the ROESY spectra in aqueous solution, the cis/trans isomerization between MePhe2-DMePhe3 and D-Cys1-MePhe2 for II and III, respectively, is observed, while in DMSO-d6, the appropriate cross peaks indicate isomerization across the Cys6-Pro7 peptide bond. In the case of the remaining peptides, the position of cis/trans isomerization is the same in aqueous solution and in dimethyl sulfoxide. [D-MePhe2,MePhe3]AVP (V) displays low antiuterotonic and antipressor activities, while [D-MePhe2,)]AVP (IV) is a weak but selective blocker of oxytocin (OT) receptors in the uterus. The former shows similar conformational preferences as another antagonist of V1a and OT receptors-namely, [Acc2,D-Arg8]VP (Acc: 1-aminocyclohexane-1-carboxylic acid)-investigated by us. In the case of IV, the cis peptide bond between residues at positions 2 and 3 might be the reason for selectivity.

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Cis/trans conformational equilibrium across the N‐methylphenylalanine²‐ N‐methylphenylalanine³ peptide bond of arginine vasopressin analogs

Cited by 12 publications

References 56 publications

The effect of N-methylation of amino acids (Ac-X-OMe) on solubility and conformation: a DFT study

The effect of N-methylation of amino acids (Ac-X-OMe) on solubility and conformation: a DFT study

Rapid Optimization of a Peptide Inhibitor of Malaria Parasite Invasion by Comprehensive N-Methyl Scanning

Conformational studies of vasopressin analogues modified with N‐methylphenylalanine enantiomers in dimethyl sulfoxide solution

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