Generation and analysis of the conformational potential energy surfaces of N-acetyl-N-methyl-l-alanine-N′-methylamide. An exploratory ab initio study

Bágyi, István; Balogh, Balázs; Czajlik, András; Éliás, Olivér; Gáspári, Zoltán; Gergely, Viktor; Hudáky, Ilona; Hudáky, Péter; Kalászi, Adrián; Károlyházy, László; Keserű, Katalin; Kiss, Robert S.; Krajsovszky, Gábor; Lang, Barbara Margarete; Nagy, Tamás Milán; Rácz, Anita; Szentesi, A.; Tábi, Tamás; Tapolcsányi, Pál; Vaik, Judit; Koo, Joseph C.P; Chass, Gregory A.; Farkas, Ödön; Perczel, András; Mátyus, Péter

doi:10.1016/s0166-1280(03)00009-5

Cited by 12 publications

(13 citation statements)

References 23 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%

“…Computational methods, [49,52] especially molecular mechanics and molecular dynamics [30,32,47,48,50,51,53] are not compensating for the smaller force constant of N-methylated amide C-N bonds, with the consequence that literature results portray a skewed picture of artificial increased rigidity for N-methylated peptides by not reflecting the increased cis/trans interconversion at room temperature.…”

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

confidence: 99%

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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%

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

confidence: 99%

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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“…4). For the N-methylalanine [35,36] as well as N-methylglycine [37] the conformer having trans arrangement of the methylated N-terminal amide group is the lowest in energy, because it is stabilised by the C7-type N--H. . .O hydrogen bond.…”

Section: Discussionmentioning

confidence: 99%

The conformation cis of N-acetyl-N-methyl-α,β-dehydroalanine N′-methylamide and saturated analogues

Siodłak¹,

Macedowska-Capiga²,

Ejsmont³

et al. 2007

Zeitschrift Für Kristallographie

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Dehydroamino acids / N-methylation / trans-cis Isomerisation / Single crystal structure analysis / X-ray diffraction Abstract. A series of three homologous amino acids derivatives: N-acetyl-N-methyl-a,b-dehydroalanine N 0 -methylamide (1), N-acetyl-N-methyl-l-alanine N 0 -methylamide (2), and N-acetyl-N-methyl-dl-alanine N 0 -methylamide have been synthesised. The racemic species undergoes spontaneous separation into l and d-enantiomers. From these two chiral forms, the structure of d-enantiomer (3) was analysed.

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“…Introduction of a tertiary amide bond into the peptide chain results in a reduction in conformational freedom of the peptide due to steric hindrance [ 27 , 28 ]. In peptides modified in this way, the tendency to adop a cis-configuration of the amide bond is frequently observed [ 29 – 31 ]. N -Methylation is a powerful means of increasing the proteolytic stability [ 32 , 33 ], membrane permeability (lipophilicity) [ 34 , 35 ], and bioavailability [ 36 ] of natural peptides.…”

Section: Introductionmentioning

confidence: 99%

The influence of solvent on conformational properties of peptides with Aib residue—a DFT study

Wałęsa

Broda

2017

J Mol Model

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The conformational propensities of the Aib residue on the example of two model peptides Ac-Aib-NHMe (1) and Ac-Aib-NMe2 (2), were studied by B3LYP and M06-2X functionals, in the gas phase and in the polar solvents. To verify the reliability of selected functionals, we also performed MP2 calculations for the tested molecules in vacuum. Polarizable continuum models (PCM and SMD) were used to estimate the solvent effect. Ramachandran maps were calculated to find all energy minima. Noncovalent intramolecular interactions due to hydrogen-bonds and dipole attractions between carbonyl groups are responsible for the relative stabilities of the conformers. In order to verify the theoretical results, the available conformations of similar X-ray structures from the Cambridge Crystallographic Data Center (CCDC) were analyzed. The results of the calculations show that both derivatives with the Aib residue in the gas phase prefer structures stabilized by intramolecular N–H⋯O hydrogen bonds, i.e., C5 and C7 conformations, while polar solvent promotes helical conformation with φ, ψ values equal to +/−60°, +/−40°. In addition, in the case of molecule 2, the helical conformation is the only one available in the polar environment. This result is fully consistent with the X-ray data. Graphical abstractEffect of solvent on the Ramachandran maps of the model peptides with Aib residue Electronic supplementary materialThe online version of this article (10.1007/s00894-017-3508-4) contains supplementary material, which is available to authorized users.

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Generation and analysis of the conformational potential energy surfaces of N-acetyl-N-methyl-l-alanine-N′-methylamide. An exploratory ab initio study

Cited by 12 publications

References 23 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

The conformation cis of N-acetyl-N-methyl-α,β-dehydroalanine N′-methylamide and saturated analogues

The influence of solvent on conformational properties of peptides with Aib residue—a DFT study

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