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

Rauf, Shah Md. Abdur; Arvidsson, Per I.; Alberício, Fernando; Govender, Thavendran; Maguire, Glenn E. M.; Kruger, Hendrik G.; Honarparvar, Bahareh

doi:10.1039/c5ob01565k

Cited by 56 publications

(21 citation statements)

References 134 publications

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“…This result is consistent with quantum mechanical calculations on the effect of N-methylation on cis/trans conversion of Ac-X-OMe amino acids, reporting an average drop of 80% in the energy difference between the cis-trans conformations after N-substitution. 51 Lowering of the force constant of the parameters acting on the ω-dihedral angle in the force field to 80% and then 60% of the original values resulted in further reductions of the transition free energy, yet maintained the free energy level of the cis state.…”

Section: Simulations Of the Open Structure Of Cyclosporin A In Chloromentioning

confidence: 99%

Conformational Flexibility Is a Determinant of Permeability for Cyclosporin

et al. 2018

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Several cyclic peptides have been reported to have unexpectedly high membrane permeability. Of these, cyclosporin A is perhaps the most well-known example, particularly in light of its relatively high molecular weight. Observations that cyclosporin A changes conformation depending on its solvent environment led to the hypothesis that conformational dynamics is a prerequisite for its permeability; however, this hypothesis has been difficult to validate experimentally. Here, we use molecular dynamics simulations to explicitly determine the conformational behavior of cyclosporin A and other related cyclic peptides as they spontaneously transition between different environments, including through a lipid bilayer. These simulations are referenced against simulations in explicit water, chloroform, and cyclohexane and further validated against NMR experiments, measuring conformational exchange, nuclear spin relaxation, and three-dimensional structures in membrane-mimicking environments, such as in dodecylphosphocholine micelles, to build a comprehensive understanding of the role of dynamics. We find that conformational flexibility is a key determinant of the membrane permeability of cyclosporin A and similar membrane-permeable cyclic peptides, as conformationally constrained variants have limited movement into, then through, and finally out of the membrane in silico. We envisage that a better understanding of dynamics might thus provide new opportunities to modulate peptide function and enhance their delivery.

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Section: Simulations Of the Open Structure Of Cyclosporin A In Chloromentioning

confidence: 99%

Conformational Flexibility Is a Determinant of Permeability for Cyclosporin

et al. 2018

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“…The frequency calculations afforded no negative Eigen values indicating stability of the molecule. After optimization of the molecules, their atomic charges were calculated using natural bond orbital (NBO) analysis, another efficient tool for studying hyperconjugative interactions, intermolecular charge transfer, and electron density transfer (EDT), which are fundamentally linked for calculations of atomic charges (Drissi et al, 2015; Md Abdur Rauf et al, 2015; El-Faham et al, 2016; Kouakou Nobel et al, 2017). …”

Section: Theoretical Calculationsmentioning

confidence: 99%

Perfluorophenyl Derivatives as Unsymmetrical Linkers for Solid Phase Conjugation

et al. 2018

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Linkers play major roles in conjugation chemistry toward the advancement of drug discovery. Two different series of fluorinated linkers were introduced to the backbone of a model peptide using solid phase peptide synthesis. These fluorinated linkers have the potential to conjugate two asymmetrical groups. This has not been done using other fluorinated linkers. This study deals with application of linkers with S, N, and O terminals and reports on the investigation of their chemoselectivity and activity for branching peptide backbones using a chosen model peptide. These fluorinated linkers have unique properties that will make it possible for a large diversity of bioconjugated chemicals for different bioapplications to be designed and synthesized.

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“…All of these modifications will impact the potential for glyphosate to be taken up by the cell and will change its reaction chemistry. For example, amino acid methylation generally makes the molecule both more water-soluble and more fat-soluble, as well as lowering the activation energy [36]. Fig.…”

Section: Nomentioning

confidence: 99%