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1. Collisional dynamics simulations revealing fragmentation properties of Zn( ii )-bound poly-peptide

   https://doi.org/10.1039/D0CP02463E  

   Malik, Abdul; Angel, Laurence A.; Spezia, Riccardo; Hase, William L. (July 2020, Physical Chemistry Chemical Physics)

   null (Ed.)

   Chemical dynamics simulations are performed to study the collision induced gas phase unimolecular fragmentation of a model peptide with the sequence acetyl-His 1 -Cys 2 -Gly 3 -Pro 4 -Tyr 5 -His 6 -Cys 7 (analogue methanobactin peptide-5, amb 5 ) and in particular to explore the role of zinc binding in reactivity. Fragmentation pathways, their mechanisms, and collision energy transfer are discussed. The probability distributions of the pathways are compared with the results of the experimental IM-MS, MS/MS spectrum and previous thermal simulations. Collisional activation gives both statistical and non-statistical fragmentation pathways with non-statistical shattering mechanisms accounting for a relevant percentage of reactive trajectories, becoming dominant at higher energies. The tetra-coordination of zinc changes qualitative and quantitative fragmentation, in particular the shattering. The collision energy threshold for the shattering mechanism was found to be 118.9 kcal mol −1 which is substantially higher than the statistical Arrhenius activation barrier of 35.8 kcal mol −1 identified previously during thermal simulations. This difference can be attributed to the tetra-coordinated zinc complex that hinders the availability of the sidechains to undergo direct collision with the Ar projectile. 

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2. Comparison of the pH‐dependent formation of His and Cys heptapeptide complexes of nickel(II), copper(II), and zinc(II) as determined by ion mobility‐mass spectrometry

   https://doi.org/10.1002/jms.4489  

   Yousef, Enas_N; Angel, Laurence_A (February 2020, Journal of Mass Spectrometry)

   Abstract The analog methanobactin (amb) peptide with the sequence ac‐His₁‐Cys₂‐Gly₃‐Pro₄‐Tyr₅‐His₆‐Cys₇(amb_5A) will bind the metal ions of zinc, nickel, and copper. To further understand how amb_5Abinds these metals, we have undertaken a series of studies of structurally related heptapeptides where one or two of the potential His or Cys binding sites have been replaced by Gly, or the C‐terminus has been blocked by amidation. The studies were designed to compare how these metals bind to these sequences in different pH solutions of pH 4.2 to 10 and utilized native electrospray ionization (ESI) with ion mobility‐mass spectrometry (IM‐MS) which allows for the quantitative analysis of the charged species produced during the reactions. The native ESI conditions were chosen to conserve as much of the solution‐phase behavior of the amb peptides as possible and an analysis of how the IM‐MS results compare with the expected solution‐phase behavior is discussed. The oligopeptides studied here have applications for tag‐based protein purification methods, as therapeutics for diseases caused by elevated metal ion levels or as inhibitors for metal‐protein enzymes such as matrix metalloproteinases. 

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3. Effect of the Tyr5 and His6 substituent groups on the zinc affinities and conformational structures of the acetyl-His1-Cys2-Gly3-Pro4-X5-X6-Cys7 heptapeptides

   https://doi.org/10.1016/j.ijms.2025.117458  

   Adomako, Richmond A; Owusu, Michael B; Oberdick, Rebekah; Senyah, Kwabena N; Asare, Perfect; Angel, Laurence A (July 2025, International Journal of Mass Spectrometry)

   In this study, we investigate the influence of the Tyr5 and His6 substituent groups on the zinc-binding affinities and conformational properties of a series of acetylated heptapeptides, acetyl-His1-Cys2-Gly3-Pro4-X5-X6-Cys7 focusing on the impacts where X5-X6 are either Tyr5-Gly6, Tyr5-His6, Gly5-Gly6, or Gly5-His6. Utilizing traveling-wave ion mobility-mass spectrometry and molecular modeling techniques we analyze the zinc binding interactions and peptide coordination behavior. The zinc binding peptides (ZBPs) relative zinc affinities were measured across pH 5 to pH 10 by monitoring the solution-phase formation of the [ZBP+Zn(II)] complex by utilizing native MS in negative ion mode to preserve the solution-phase binding of Zn(II) to the peptides. Furthermore, their relative gas-phase Zn(II) affinities were measured using competitive threshold collision-induced dissociation (TCID) of the [ZBP+Zn(II)+NTA] complex, by modeling the two competing dissociation channels: [ZBP+Zn(II)]- + NTA or [Zn(II)+NTA] + ZBP, where NTA is nitrilotriacetic acid. Our examinations also tested whether there was an effect of the formation of the [ZBP+Zn(II)+NTA] complexes from solutions at different pHs, before they are electrosprayed into the gas-phase for the TCID analyses. Both solution- and gas-phase measurements predicted the heptapeptide with the Gly5-His6 residues had the greatest zinc affinity and that the presence of Tyr5 and His6 altered the zinc affinity and induced distinct conformational changes due to changes in the coordination of the zinc. This research enhances our understanding of zinc-peptide interactions, with implications for the design of peptide-based metalloproteins, which may guide the design of novel ZBPs for therapeutic, biotechnological or environmental remediation applications. 

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4. Targeting EGFR Overexpression at the Surface of Colorectal Cancer Cells by Exploiting Amidated BODIPY‐Peptide Conjugates

   https://doi.org/10.1111/php.13234  

   Williams, Tyrslai M.; Zhou, Zehua; Singh, Sitanshu S.; Sibrian‐Vazquez, Martha; Jois, Seetharama D.; Henriques Vicente, Maria da Graça (April 2020, Photochemistry and Photobiology)

   Abstract Three BODIPY‐peptide conjugates designed to target the epidermal growth factor receptor (EGFR) at the extracellular domain were synthesized, and their specificity for binding to EGFR was investigated. Peptide sequences containing seven amino acids, GLARLLT (2)and KLARLLT (4), and 13 amino acids, GYHWYGYTPQNVI (3), were conjugated to carboxyl BODIPY dye (1) by amide bond formation in up to 73% yields. The BODIPY‐peptide conjugates and their “parent” peptides were determined to bind to EGFR experimentally using SPR analysis and were further investigated using computational methods (AutoDock). Results of SPR, competitive binding and docking studies propose that conjugate6including the GYHWYGYTPQNVI sequence binds to EGFR more effectively than conjugates5and7, bearing the smaller peptide sequences. Findings in human carcinoma HEp2 cells overexpressing EGFR showed nontoxic behavior in the presence of activated light (1.5 J cm⁻²) and in the absence of light for all BODIPYs. Furthermore, conjugate6showed about five‐fold higher accumulation within HEp2 cells compared with conjugates5and7, localizing preferentially in the cell ER and lysosomes. Our findings suggest that BODIPY‐peptide conjugate6is a promising contrast agent for detection of colorectal cancer and potentially other EGFR‐overexpressing cancers. 

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5. Zn-Enhanced Asp-Rich Antimicrobial Peptides: N-Terminal Coordination by Zn(II) and Cu(II), Which Distinguishes Cu(II) Binding to Different Peptides

   https://doi.org/10.3390/ijms22136971  

   Miller, Adriana; Matera-Witkiewicz, Agnieszka; Mikołajczyk, Aleksandra; Wątły, Joanna; Wilcox, Dean; Witkowska, Danuta; Rowińska-Żyrek, Magdalena (July 2021, International Journal of Molecular Sciences)

   null (Ed.)

   The antimicrobial activity of surfactant-associated anionic peptides (SAAPs), which are isolated from the ovine pulmonary surfactant and are selective against the ovine pathogen Mannheimia haemolytica, is strongly enhanced in the presence of Zn(II) ions. Both calorimetry and ITC measurements show that the unique Asp-only peptide SAAP3 (DDDDDDD) and its analogs SAAP2 (GDDDDDD) and SAAP6 (GADDDDD) have a similar micromolar affinity for Zn(II), which binds to the N-terminal amine and Asp carboxylates in a net entropically-driven process. All three peptides also bind Cu(II) with a net entropically-driven process but with higher affinity than they bind Zn(II) and coordination that involves the N-terminal amine and deprotonated amides as the pH increases. The parent SAAP3 binds Cu(II) with the highest affinity; however, as shown with potentiometry and absorption, CD and EPR spectroscopy, Asp residues in the first and/or second positions distinguish Cu(II) binding to SAAP3 and SAAP2 from their binding to SAAP6, decreasing the Cu(II) Lewis acidity and suppressing its square planar amide coordination by two pH units. We also show that these metal ions do not stabilize a membrane disrupting ability nor do they induce the antimicrobial activity of these peptides against a panel of human pathogens. 

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