Bilayer thickness determines the alignment of model polyproline helices in lipid membranes

Kubyshkin, Vladimir; Grage, Stephan L.; Ulrich, Anne S.; Budiša, Nediljko

doi:10.1039/c9cp02996f

Cited by 7 publications

(5 citation statements)

References 71 publications

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“…Although it is hydrophobic in nature, the halogen introduces some interesting physico-chemical features not normally associated with this property, such as allowing for the possibility of F···H–N hydrogen bond formation. This is confirmed by through-space coupling in NMR studies [ 17 , 18 ].…”

Section: The Structural and Physico-chemical Effects Of Halogen Atoms In Polypeptidesmentioning

confidence: 54%

“…Furthermore, halogenation, such tryptophan bromination, resulted to be useful to optimize [ 221 ] the characteristics of bioactive molecules with pharmaceutical activity, as shown for products from marine organisms. Fluorine is efficaciously used as an internal probe for F 19 -NMR studies of peptide and protein structure-activity relationships (SAR), especially in interaction with biological membranes [ 18 , 222 ]. SAR studies have also revealed a correlation between the enhanced hydrophobicity resulting from halogenation and the antimicrobial activity of AMPs and their pep-tidomimetics.…”

Section: Future Perspectives and Conclusionmentioning

confidence: 99%

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Natural and Synthetic Halogenated Amino Acids—Structural and Bioactive Features in Antimicrobial Peptides and Peptidomimetics

Mardirossian

Rubini

Adamo³

et al. 2021

Molecules

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The 3D structure and surface characteristics of proteins and peptides are crucial for interactions with receptors or ligands and can be modified to some extent to modulate their biological roles and pharmacological activities. The introduction of halogen atoms on the side-chains of amino acids is a powerful tool for effecting this type of tuning, influencing both the physico-chemical and structural properties of the modified polypeptides, helping to first dissect and then rationally modify features that affect their mode of action. This review provides examples of the influence of different types of halogenation in amino acids that replace native residues in proteins and peptides. Examples of synthetic strategies for obtaining halogenated amino acids are also provided, focusing on some representative compounds and their biological effects. The role of halogenation in native and designed antimicrobial peptides (AMPs) and their mimetics is then discussed. These are in the spotlight for the development of new antimicrobial drugs to counter the rise of antibiotic-resistant pathogens. AMPs represent an interesting model to study the role that natural halogenation has on their mode of action and also to understand how artificially halogenated residues can be used to rationally modify and optimize AMPs for pharmaceutical purposes.

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Section: The Structural and Physico-chemical Effects Of Halogen Atoms In Polypeptidesmentioning

confidence: 54%

Section: Future Perspectives and Conclusionmentioning

confidence: 99%

Natural and Synthetic Halogenated Amino Acids—Structural and Bioactive Features in Antimicrobial Peptides and Peptidomimetics

Mardirossian

Rubini

Adamo³

et al. 2021

Molecules

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“…The answer is ‘yes’. Very recently we demonstrated experimentally that the polyproline-II helix can be integrated to the membrane and adopt a defined transmembrane alignment [62,63]. A successive study showed that the collagen helix, a fold made out of assembled polyproline-II helices, has no fundamental limitations to do so as well [64].…”

Section: The Proline Worldmentioning

confidence: 99%

The Alanine World Model for the Development of the Amino Acid Repertoire in Protein Biosynthesis

Kubyshkin

Budiša

2019

IJMS

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A central question in the evolution of the modern translation machinery is the origin and chemical ethology of the amino acids prescribed by the genetic code. The RNA World hypothesis postulates that templated protein synthesis has emerged in the transition from RNA to the Protein World. The sequence of these events and principles behind the acquisition of amino acids to this process remain elusive. Here we describe a model for this process by following the scheme previously proposed by Hartman and Smith, which suggests gradual expansion of the coding space as GC–GCA–GCAU genetic code. We point out a correlation of this scheme with the hierarchy of the protein folding. The model follows the sequence of steps in the process of the amino acid recruitment and fits well with the co-evolution and coenzyme handle theories. While the starting set (GC-phase) was responsible for the nucleotide biosynthesis processes, in the second phase alanine-based amino acids (GCA-phase) were recruited from the core metabolism, thereby providing a standard secondary structure, the α-helix. In the final phase (GCAU-phase), the amino acids were appended to the already existing architecture, enabling tertiary fold and membrane interactions. The whole scheme indicates strongly that the choice for the alanine core was done at the GCA-phase, while glycine and proline remained rudiments from the GC-phase. We suggest that the Protein World should rather be considered the Alanine World, as it predominantly relies on the alanine as the core chemical scaffold.

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“…The presence of these groups adjacent to the proline structure helps to modulate the conformational landscape of the parent amino acid, and this effectively alters the folding of the peptide chain when an analogue is included in it as a residue [49,50]. The presence of a fluorine-rich group in the structure is also beneficial for the NMR studies based on the detection of the 19 F nucleus [51][52][53]. Limited attention has been given to the polarity effects in the proline analogues though.…”

Section: Introductionmentioning

confidence: 99%

Polarity effects in 4-fluoro- and 4-(trifluoromethyl)prolines

Kubyshkin¹

2020

Beilstein J. Org. Chem.

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Fluorine-containing analogues of proline are valuable tools in engineering and NMR spectroscopic studies of peptides and proteins. Their use relies on the fundamental understanding of the interplay between the substituents and the main chain groups of the amino acid residue. This study aims to showcase the polarity-related effects that arise from the interaction between the functional groups in molecular models. Properties such as conformation, acid–base transition, and amide-bond isomerism were examined for diastereomeric 4-fluoroprolines, 4-(trifluoromethyl)prolines, and 1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylates. The preferred conformation on the proline ring originated from a preferential axial positioning for a single fluorine atom, and an equatorial positioning for a trifluoromethyl- or a difluoromethylene group. This orientation of the substituents explains the observed trends in the pK a values, lipophilicity, and the kinetics of the amide bond rotation. The study also provides a set of evidences that the transition state of the amide-bond rotation in peptidyl-prolyl favors C4-exo conformation of the pyrrolidine ring.

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Bilayer thickness determines the alignment of model polyproline helices in lipid membranes

Abstract: We describe the design and experimental observation of an entirely new transmembrane helical peptide motif.

Cited by 7 publications

References 71 publications

Natural and Synthetic Halogenated Amino Acids—Structural and Bioactive Features in Antimicrobial Peptides and Peptidomimetics

Natural and Synthetic Halogenated Amino Acids—Structural and Bioactive Features in Antimicrobial Peptides and Peptidomimetics

The Alanine World Model for the Development of the Amino Acid Repertoire in Protein Biosynthesis

Polarity effects in 4-fluoro- and 4-(trifluoromethyl)prolines

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