Electrostatically induced pKa shifts in oligopeptides: the upshot of neighboring side chains

Norouzy, Amir; Lazăr, Alexandra; Karimi‐Jafari, Mohammad Hossein; Firouzi, Rohoullah; Nau, Werner M.

doi:10.1007/s00726-021-03116-2

Cited by 7 publications

(4 citation statements)

References 40 publications

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“…The determined pK a values of the sequences ranged from 6.94 for PEG2K-PHis20 to 6.97 for PEG2K-PHis26, with a slightly higher value of 7.01 for PEG2K-PHis32 ( Figure S4 ). These data were in agreement with previously reported pK a values of PEG-PHis systems synthesized using ring-opening polymerization [ 34 , 38 ] and were slightly higher when compared with the polyhistidine homopolymer due to increased hydration of the PEG [ 52 ]. The obtained pK a values provided by the amphoteric nature of imidazole of the PEG2K-PHis sequences suggested their pH-sensitive behavior.…”

Section: Resultssupporting

confidence: 92%

Solid-Phase Synthesized Copolymers for the Assembly of pH-Sensitive Micelles Suitable for Drug Delivery Applications

Ghiarasim¹,

Tiron

et al. 2022

Nanomaterials

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Diblock copolymers of polyhistidine are known for their self-assembly into micelles and their pH-dependent disassembly due to the amphiphilic character of the copolymer and the unsaturated imidazole groups that undergo a hydrophobic-to-hydrophilic transition in an acidic pH. This property has been largely utilized for the design of drug delivery systems that target a tumor environment possessing a slightly lower extracellular pH (6.8–7.2). The main purpose of this study was to investigate the possibility of designed poly(ethylene glycol)-polyhistidine sequences synthesized using solid-phase peptide synthesis (SPPS), to self-assemble into micelles, to assess the ability of the corresponding micelles to be loaded with doxorubicin (DOX), and to investigate the drug release profile at pH values similar to a malignant extracellular environment. The designed and assembled free and DOX-loaded micelles were characterized from a physico-chemical point of view, their cytotoxicity was evaluated on a human breast cancer cell line (MDA-MB-231), while the cellular areas where micelles disassembled and released DOX were assessed using immunofluorescence. We concluded that the utilization of SPPS for the synthesis of the polyhistidine diblock copolymers yielded sequences that behaved similarly to the copolymeric sequences synthesized using ring-opening polymerization, while the advantages of SPPS may offer facile tuning of the histidine site or the attachment of a large variety of functional molecules.

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Section: Resultssupporting

confidence: 92%

Solid-Phase Synthesized Copolymers for the Assembly of pH-Sensitive Micelles Suitable for Drug Delivery Applications

Ghiarasim¹,

Tiron

et al. 2022

Nanomaterials

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“…We find that, depending on its deprotonated/protonated state and the proximity to nucleophilic water/Ser70:O γ , carbamylated Lys73 plays different roles at different stages of the hydrolysis reaction. This is a prevalent feature of ionizable residues in the protein environment. − In fact, our previous study on acylation and deacylation mechanisms of class C β-lactamases also showed that a lysine residue in the active site can act as both base and acid depending on the dynamic changes in the environment. , …”

Section: Resultsmentioning

confidence: 99%

Inhibition Mechanism of Class D β-Lactamases by Avibactam

2022

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Escalation of antibiotic resistance due to class D β-lactamases (DBLs) carrying bacteria is a matter of grave concern. This class of enzymes can efficiently hydrolyze the carbapenem group of antibiotics that are the last-reserved therapeutics for infections caused by multidrug-resistant bacteria. The development of efficient inhibitors against DBLs calls for a molecular-level understanding of the hydrolysis mechanism. Here, we investigate the mechanism of inhibition of OXA-48 DBL enzyme by one of the diazobicyclooctane class of inhibitors, namely avibactam, through molecular dynamics simulations and free energy calculations. Hydrolysis as well as inhibition mechanisms are expected to be intricate due to the presence of N-carbamylated lysine (Lys73), multiple acidic and basic active site residues, and active site water molecules. Our extensive mechanistic study characterizes the most probable reaction route and critical reaction intermediates starting from the acylation to the full hydrolysis of the covalent intermediate. This study discerns the residues that act as the general bases at different steps. Free energies and reaction intermediate structures are corroborated with the available experimental kinetics data and crystal structures. We also simulated the deacylation of a β-lactam drug, namely meropenem, which is known to be hydrolyzed efficiently by the enzyme. By comparing the mechanism of meropenem hydrolysis with that of avibactam, our study reveals the important chemical features that are useful for designing inhibitors.

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“…DFRET is just one method in a whole range of optical methods for studying the structure and dynamics of polymers [ 10 , 11 , 12 , 13 , 14 , 17 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 ]. When we go into detail, we realize that any progress in DFRET can synergistically promote progress in this entire field [ 13 ].…”

Section: Discussionmentioning

confidence: 99%

Diffusion-Enhanced Förster Resonance Energy Transfer in Flexible Peptides: From the Haas-Steinberg Partial Differential Equation to a Closed Analytical Expression

et al. 2023

Self Cite

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In the huge field of polymer structure and dynamics, including intrinsically disordered peptides, protein folding, and enzyme activity, many questions remain that cannot be answered by methodology based on artificial intelligence, X-ray, or NMR spectroscopy but maybe by fluorescence spectroscopy. The theory of Förster resonance energy transfer (FRET) describes how an optically excited fluorophore transfers its excitation energy through space to an acceptor moiety—with a rate that depends on the distance between donor and acceptor. When the donor and acceptor moiety are conjugated to different sites of a flexible peptide chain or any other linear polymer, the pair could in principle report on chain structure and dynamics, on the site-to-site distance distribution, and on the diffusion coefficient of mutual site-to-site motion of the peptide chain. However, the dependence of FRET on distance distribution and diffusion is not defined by a closed analytical expression but by a partial differential equation (PDE), by the Haas-Steinberg equation (HSE), which can only be solved by time-consuming numerical methods. As a second complication, time-resolved FRET measurements have thus far been deemed necessary. As a third complication, the evaluation requires a computationally demanding but indispensable global analysis of an extended experimental data set. These requirements have made the method accessible to only a few experts. Here, we show how the Haas-Steinberg equation leads to a closed analytical expression (CAE), the Haas-Steinberg-Jacob equation (HSJE), which relates a diffusion-diagnosing parameter, the effective donor–acceptor distance, to the augmented diffusion coefficient, J, composed of the diffusion coefficient, D, and the photophysical parameters that characterize the used FRET method. The effective donor–acceptor distance is easily retrieved either through time-resolved or steady-state fluorescence measurements. Any global fit can now be performed in seconds and minimizes the sum-of-square difference between the experimental values of the effective distance and the values obtained from the HSJE. In summary, the HSJE can give a decisive advantage in applying the speed and sensitivity of FRET spectroscopy to standing questions of polymer structure and dynamics.

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Electrostatically induced pKa shifts in oligopeptides: the upshot of neighboring side chains

Cited by 7 publications

References 40 publications

Solid-Phase Synthesized Copolymers for the Assembly of pH-Sensitive Micelles Suitable for Drug Delivery Applications

Solid-Phase Synthesized Copolymers for the Assembly of pH-Sensitive Micelles Suitable for Drug Delivery Applications

Inhibition Mechanism of Class D β-Lactamases by Avibactam

Diffusion-Enhanced Förster Resonance Energy Transfer in Flexible Peptides: From the Haas-Steinberg Partial Differential Equation to a Closed Analytical Expression

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