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© 2023 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/), Most antimicrobial peptides (AMPs) exert their microbicidal activity through membrane permeabilization. The designed AMP EcDBS1R4 has a cryptic mechanism of action involving the membrane hyperpolarization of Escherichia coli, suggesting that EcDBS1R4 may hinder processes involved in membrane potential dissipation. We show that EcDBS1R4 can sequester cardiolipin, a phospholipid that interacts with several respiratory complexes of E. coli. Among these, F1FO ATP synthase uses membrane potential to fuel ATP synthesis. We found that EcDBS1R4 can modulate the activity of ATP synthase upon partition to membranes containing cardiolipin. Molecular dynamics simulations suggest that EcDBS1R4 alters the membrane environment of the transmembrane FO motor, impairing cardiolipin interactions with the cytoplasmic face of the peripheral stalk that binds the catalytic F1 domain to the FO domain. The proposed mechanism of action, targeting membrane protein function through lipid reorganization may open new venues of research on the mode of action and design of other AMPs.

Inception: the 3D-BioInfo-PT project is born, partially as a re-branding under Biodata.pt of the community involved in the EJIBCE meetings – Encontros de Jovens Investigadores em Biologia Computacional Estrutural. Materialization: Planned roadmap presented and debated at the Biodata.pt Technical Meeting. Teaching: the first 3D-BioInfo-PT workshop takes place at ITQB NOVA. It is an event with 35 participants (out of 62 applicants) hailing from 7 different institutions. Main support from the Oeiras Valley initiative and Wallfuture Lda. Continuity: maintain the 3D Biotalks seminar cycle and expand its reach. Networking: maintain the EJIBCE tradition of the annual meeting. Organize a satellite workshop. Collaboration: bring together the 3D-BioInfo-PT coordinating groups to write a perspective article on computational structural research in Portugal., https://3d-bioinfo-pt.github.io/

Copyright © 2021 Mink, Strandberg, Wadhwani, Melo, Reichert, Wacker, Castanho and Ulrich. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms., BP100 is a short, designer-made membrane-active peptide with multiple functionalities: antimicrobial, cell-penetrating, and fusogenic. Consisting of five lysines and 6 hydrophobic residues, BP100 was shown to bind to lipid bilayers as an amphipathic a-helix, but its mechanism of action remains unclear. With these features, BP100 embodies the characteristics of two distinctly different classes of membrane-active peptides, which have been studied in detail and where the mechanism of action is better understood. On the one hand, its amphiphilic helical structure is similar to the pore forming magainin family of antimicrobial peptides, though BP100 is much too short to span the membrane. On the other hand, its length and high charge density are reminiscent of the HIV-TAT family of cell penetrating peptides, for which inverted micelles have been postulated as translocation intermediates, amongst other mechanisms. Assays were performed to test the antimicrobial and hemolytic activity, the induced leakage and fusion of lipid vesicles, and cell uptake. From these results the functional profiles of BP100, HIV-TAT, and the magainin-like peptides magainin 2, PGLa, MSI-103, and MAP were determined and compared. It is observed that the activity of BP100 resembles most closely the much longer amphipathic a-helical magainin-like peptides, with high antimicrobial activity along with considerable fusogenic and hemolytic effects. In contrast, HIV-TAT shows almost no antimicrobial, fusogenic, or hemolytic effects. We conclude that the amphipathic helix of BP100 has a similar membranebased activity as magainin-like peptides and may have a similar mechanism of action., This work was supported financially by the BIF-TM program of the Helmholtz-Gemeinschaft; by the DFG grant INST 121384/58-1 FUGG; and by the DAAD “Portugal - Acções Integradas Luso-Alemãs/DAAD-GRIC” grant D/07/13644.

Tese de doutoramento, Bioquímica (Biofísica Molecular), Universidade de Lisboa, Faculdade de Ciências, 2010 Submitted by Marta Nogueira (mnogueira@reitoria.ul.pt) on 2010-10-25T16:53:33Z No. of bitstreams: 1 Tese_Thesis_MNMelo.pdf: 5876637 bytes, checksum: ec17dd982b23c7b94f7d0bd866c4bdf7 (MD5) Made available in DSpace on 2010-10-25T16:54:49Z (GMT). No. of bitstreams: 1 Tese_Thesis_MNMelo.pdf: 5876637 bytes, checksum: ec17dd982b23c7b94f7d0bd866c4bdf7 (MD5) Previous issue date: 2010 Fundação para a Ciência e Tecnologia / Foundation for Science and Technology - SFRH/BD/24778/2005; Portuguese National Conference of Rectors

© 2018 American Chemical Society, Measles remains one of the leading causes of child mortality worldwide and is re-emerging in some countries due to poor vaccine coverage, concomitant with importation of measles virus (MV) from endemic areas. The lack of specific chemotherapy contributes to negative outcomes, especially in infants or immunodeficient individuals. Fusion inhibitor peptides derived from the MV Fusion protein C-terminal Heptad Repeat (HRC) targeting MV envelope fusion glycoproteins block infection at the stage of entry into host cells, thus preventing viral multiplication. To improve efficacy of such entry inhibitors, we have modified a HRC peptide inhibitor by introducing properties of self-assembly into nanoparticles (NP) and higher affinity for both viral and cell membranes. Modification of the peptide consisted of covalent grafting with tocopherol to increase amphipathicity and lipophilicity (HRC5). One additional peptide inhibitor consisting of a peptide dimer grafted to tocopherol was also used (HRC6). Spectroscopic, imaging, and simulation techniques were used to characterize the NP and explore the molecular basis for their antiviral efficacy. HRC5 forms micellar stable NP while HRC6 aggregates into amorphous, loose, unstable NP. Interpeptide cluster bridging governs NP assembly into dynamic metastable states. The results are consistent with the conclusion that the improved efficacy of HRC6 relative to HRC5 can be attributed to NP instability, which leads to more extensive partition to target membranes and binding to viral target proteins., This work was supported by Fundação para a Ciência e a Tecnologia (FCT-MCTES) Project PTDC/QEQ-MED/4412/2014. T.N.F., D.A.M,. and D.G. acknowledge individual fellowships SFRH/BD/5283/2013, PD/BD/ 136752/2018 and SFRH/BPD/109010/2015 funded by FCT-MCTES. A.S.V. acknowledges funding under the Investigator Programme (IF/00803/2012) from FCTMCTES. M.N.M. acknowledges Grant LISBOA-01-0145- FEDER-007660 (Microbiologia Molecular, Estrutural e Celular) funded by Fundo Europeu de Desenvolvimento Regional (FEDER) and FCT-MCTES. A.M. acknowledges Grants RO1AI114736, R33AI101333, and RO1AI031971, and M.P. acknowledges grants R01AI119762, R01AI121349, and R01NS105699 funded by the National Institutes of Health (NIH).