Mechanisms of action of ribosomally synthesized and posttranslationally modified peptides (RiPPs)

Cao, Li; Do, Truc; Link, A. James

doi:10.1093/jimb/kuab005

Cited by 75 publications

(77 citation statements)

References 252 publications

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“…We adopted Boltzmann averaging due to its relevance to characterize energy state of canonical ensemble in thermodynamic equilibrium. 83,84 The computed energy gap of 2.7 kcal/mol is consistent with the experimental trend for ∆H (i.e., 4 kcal/mol). The agreement is particularly good considering that we neglected vibrational zero-point energy corrections due to the high cost of computing Hessians for such large systems.…”

Section: Results and Discussion 3a Loss Of Hydrogen Bonding Interactions Elevates The Energy State Of Conformersupporting

confidence: 78%

Computational Modeling of Conformer Stability in Benenodin-1, A Thermally-Actuated Lasso Peptide Switch

Yang

Hajlasz

Kulik

2022

Preprint

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Benenodin-1 is a thermally-actuated lasso peptide rotaxane switch with two primary translational isomers that differ in the relative position of residue Gln15. The conversion from one conformer to the other involves substantial enthalpy-entropy compensation: one conformer is energetically-favored and the other is entropically-favored. Here, we take a multi-scale quantum mechanical (QM) and classical molecular dynamics (MD) approach to reveal residue-specific sources of these differences in stability. QM reveals that the two benenodin-1 conformers involve distinct hydrogen bonding networks, with the enthalpically-favored conformer having more intra-peptide hydrogen bonds between Gln15 sidechain and nearby residues. Evaluation of configurational entropy over the MD-sampled geometries reveals that the entropically-favored conformer has enhanced conformational flexibility. By computing the by-residue-sum entropies, we identify the role of Gln15 and neighboring Glu14 in mediating the entropic variation during the switching process. These computational insights help explain the effects of Glu14Ala and Gln15Ala mutations on the conformational population of benenodin-1 observed experimentally.

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Section: Results and Discussion 3a Loss Of Hydrogen Bonding Interactions Elevates The Energy State Of Conformersupporting

confidence: 78%

Computational Modeling of Conformer Stability in Benenodin-1, A Thermally-Actuated Lasso Peptide Switch

Yang

Hajlasz

Kulik

2022

Preprint

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“…Thiazolines and thiazole are replete in natural products 42–44 and synthetic drug-like small molecules, 8,9 and calculations confirm the expected decrease in conformational freedom that derives from aromatic and/or sp 2 character within the peptide backbone. 45 This finding and the leader-independent nature of MicD-F and ArtGox-mediated thiazol(in)e biosynthesis inspired us to explore substrates in which the site of cyclodehydration/dehydrogenation is embedded within a stable protein fold ( Figure 4 ).…”

Section: Resultsmentioning

confidence: 87%

Redirecting RiPP biosynthetic enzymes to proteins and backbone-modified substrates

Walker¹,

Hamlish²,

Tytla³

et al. 2022

Preprint

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Ribosomally synthesized and post-translationally modified peptides (RiPPs) are peptide-derived natural products that include the FDA-approved analgesic ziconotide1,2 as well as compounds with potent antibiotic, antiviral, and anticancer properties.3 RiPP enzymes known as cyclodehydratases and dehydrogenases represent an exceptionally well-studied enzyme class.3 These enzymes work together to catalyze intramolecular, interresidue condensation3,4 and aromatization reactions that install oxazoline/oxazole and thiazoline/thiazole heterocycles within ribosomally produced polypeptide chains. Here we show that the previously reported enzymes MicD-F and ArtGox accept backbone-modified monomers, including aramids and beta-amino acids, within leader-free polypeptides, even at positions immediately preceding or following the site of cyclization/dehydrogenation. The products are sequence-defined chemical polymers with multiple, diverse, non-alpha-amino acid subunits. We show further that MicD-F and ArtGox can install heterocyclic backbones within protein loops and linkers without disrupting the native tertiary fold. Calculations reveal the extent to which these heterocycles restrict conformational space; they also eliminate a peptide bond. Both features could improve the stability or add function to linker sequences now commonplace in emerging biotherapeutics. Moreover, as thiazoles and thiazoline heterocycles are replete in natural products,5,6,7 small molecule drugs,8,9 and peptide-mimetic therapeutics,10 their installation in protein-based biotherapeutics could improve or augment performance, activity, stability, and/or selectivity. This work represents a general strategy to expand the chemical diversity of the proteome beyond and in synergy with what can now be accomplished by expanding the genetic code.

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“…Therefore, the first two residues IL1 and Dhb2 associated with N-ter lanthhionine ring A and methyl lanthionine ringB forms a pocket that encloses the lipidII. This interaction is ensured by the hydrogen binding between the pyrophosphate group of lipidII and the backbone amides [26] (Figure 5). Wiedemann et al have demonstrated that C-terminal region is crucial for binding to membrane with a negative surface charge.…”

Section: Structural Analysis: Amino Acids and Activitymentioning

confidence: 99%

“…The study of bacteriocin structures and amino acids composition helps to understand their detailed mechanism of action. This feature is critical towards the development of bacteriocins as therapeutics and can also be used to prioritize hits in their genome mining studies [26]. Hence a library of synthetic bacteriocin variants served as a tool; to recognize key residues responsible for activity and could continue to inspire the development of new therapeutic agents [27].…”

Section: Introductionmentioning

confidence: 99%

Anti-Microbial Peptides: The Importance of Structure-Function Analysis in the Design of New AMPs

Ouertani¹,

Mosbah²,

Chérif³

2022

Insights on Antimicrobial Peptides

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In recent years the rapid emergence of drug resistant microorganisms has become a major health problem worldwide. The number of multidrug resistant (MDR) bacteria is in a rapid increase. Therefore, there is an urgent need to develop new antimicrobial agent that is active against MDR. Among the possible candidates, antimicrobial peptides (AMPs) represent a promising alternative. Many AMPs candidates were in clinical development and the Nisin was approved in many food products. Exact mechanism of AMPs action has not been fully elucidated. More comprehensive of the mechanism of action provide a path towards overcoming the toxicity limitation. This chapter is a review that provides an overview of bacterial AMPs named bacteriocin, focusing on their diverse mechanism of action. We develop here the structure–function relationship of many AMPs. A good understanding of AMPS structure–function relationship can helps the scientific in the conception of new active AMPs by the evaluation of the role of each residue and the determination of the essential amino acids for activity. This feature helps the development of the second-generation AMPs with high potential antimicrobial activity and more.

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Mechanisms of action of ribosomally synthesized and posttranslationally modified peptides (RiPPs)

Cited by 75 publications

References 252 publications

Computational Modeling of Conformer Stability in Benenodin-1, A Thermally-Actuated Lasso Peptide Switch

Computational Modeling of Conformer Stability in Benenodin-1, A Thermally-Actuated Lasso Peptide Switch

Redirecting RiPP biosynthetic enzymes to proteins and backbone-modified substrates

Anti-Microbial Peptides: The Importance of Structure-Function Analysis in the Design of New AMPs

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