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Molecular modelling for studying molecular mechanisms of antibacterial and antiviral activity of cationic photosensitizersстатья
Статья опубликована в высокорейтинговом журнале
Статья опубликована в журнале из списка Web of Science и/или ScopusДата последнего поиска статьи во внешних источниках: 19 июня 2024 г.
- Авторы: Kholina E.G., Fedorov V.A., Khruschev S.S., Kovalenko I.B., Strakhovskaya M.G., Rubin A.B.
- Журнал: Biophysical Reviews
- Том: 15
- Год издания: 2023
- Издательство: Springer Verlag
- Местоположение издательства: Germany
- Первая страница: 1456
- Последняя страница: 1457
- DOI: 10.1007/s12551-023-01150-w
- Аннотация: Photodynamic inactivation, which uses photoactivated biocides – pho- tosensitizers, is an approach to combat antimicrobial-resistant patho- gens. In addition to their bactericidal action, cationic photosensitiz- ers are highly effective against enveloped viruses. Octakis(cholinyl) zinc phthalocyanine (PC) is one of the most effective photosensitizers against a broad spectrum of pathogens including enveloped viruses. The aim of this work was to study intermolecular interactions dur- ing the binding of PCs to the envelope components and its transport through the membrane structures of microorganisms.To study the molecular nature underlying the antibacterial activity of PC, coarse-grained molecular dynamics was applied. Using the umbrella sampling technique, we described the process of PC translo- cation through bacterial membranes and demonstrated high affinity of PC to bacterial membranes. We found out that this process is energeti- cally favorable and leads to overall disturbance of the model bilayer and formation of the aqueous pore. The results of our simulations con- firmed the hypothesis of PC “self-promoted uptake” inside the outer bacterial lipopolysaccharide membrane and explained the molecular nature of PC antibacterial activity [1].To study the antiviral activity of cationic photosensitizers and identify their binding sites on the viral envelope, we calculated distribution of electrostatic potential on the surface of S proteins of three coronavi- ruses [2,3] and the whole SARS-CoV-2 [4] and performed Brownian dynamics calculations. We obtained several thousand of electrostati- cally favorable encounter complexes of PC molecule with each of the coronavirus S protein and reveal the major binding site for all S pro- teins, located at the junction of the “stem” and the “head” at a distance of about 10 nm from the viral membrane. Since the diffusion distance of singlet oxygen generated by PS is 10–55 nm, it can cause oxidative damage to both the S proteins themselves and the lipid bilayer of viri- ons, and thereby virus inactivation.The next stage of the study was to study the interaction of PC with the whole model of the SARS-CoV-2 envelope. Using a coarse-grained model of the entire viral envelope developed by D. Korkin and S.-J. Marrink’s scientific groups [5], we created an electrostatic map of the external surface of SARS-CoV-2 and found a highly heterogeneous distribution of the electrostatic potential field of the viral envelope [5]. Numerous negative patches originate mainly from negatively charged lipid molecules POPI (-1), POPS (-1), CDL2 (-2) and negatively charged amino acids of S proteins. To investigate which components of SARS-CoV-2 viral membrane attract PC molecule, we performed 40 thousand independent Brownian dynamics simulations of PC molecule relative to immobile viral envelope. About 43% of the PC molecules were found in encounter complexes with proteins of viral envelope. Among them, about 80% formed electrostatic contacts with S proteins. In the remaining 57% of the complexes of PC molecules, close con- tacts with membrane proteins are not required, and they were bound to negatively charged lipids only. Thus, all negatively charged components attract photosensitizer molecules and are potential targets for singlet oxygen generated by PS molecules. The theoretical results obtained by computer modelling are consistent with the previously observed spike loss and membrane destruction, as a result of the photodynamic inactivation of the coronavirus with the same PS. Thus, the study of the detailed electrostatic map of the whole virion using a computer model provides unique opportunities to reveal the binding sites of charged molecules on the surface of the virus.Application of computer modeling methods made it possible to describe specific pathways for the transfer of cationic photosensitiz- ers through the bacterial cell wall and to identify the binding areas of photosensitizers on the viral envelope. Knowledge of the molecular details underlying the antiviral and antibacterial activity of biocides contributes to their rational use for medical purposes and necessary for the design of new effective antimicrobial compounds.References1. Orekhov P. S. Molecular mechanism of uptake of cationic photoan- timicrobial phthalocyanine across bacterial membranes revealed by molecular dynamics simulations / P. S. Orekhov, E. G. Kholina, M. E. Bozdaganyan, A. M. Nesterenko, I. B. Kovalenko, M. G. Strakhovskaya // J. Phys. Chem. B. 2018. V. 122. No 14. P. 3711—3722.2. Sharshov K. The photosensitizer octakis (Cholinyl) zinc phthalo- cyanine with ability to bind to a model spike protein leads to a loss of SARS-CoV-2 infectivity in vitro when exposed to far-red LED / K. Sharshov, M. Solomatina, O. Kurskaya, I. Kovalenko, E. Kholina, V. Fedorov, G. Meerovich, A. Rubin, M. Strakhovskaya // Viruses. 2021. V.13.No4.P.643.3. Fedorov V. What Binds Cationic Photosensitizers Better: Brownian Dynamics Reveals Key Interaction Sites on Spike Proteins of SARS- CoV, MERS-CoV, and SARS-CoV-2 / V. Fedorov, E. Kholina, S. Khr- uschev, I. Kovalenko, A. Rubin, M. Strakhovskaya // Viruses. 2021. V. 13. No 8. P. 1615.4. Fedorov V. Electrostatic Map of the SARS-CoV-2 Virion Specifies Binding Sites of the Antiviral Cationic Photosensitizer / V. Fedorov, E. Kholina, S. Khruschev, I. Kovalenko, A. Rubin, M. Strakhovskaya // Int. J. Mol. Sci. 2022. V. 23. No 13. P. 7304.5. Pezeshkian W. Molecular architecture and dynamics of SARS-CoV-2 envelope by integrative modeling / W. Pezeshkian, F. Grünewald, O. Narykov, S. Lu, T.A. Wassenaar, S.J. Marrink, D. Korkin // bioRxiv. 2022. P. 2021.09.
- Добавил в систему: Федоров Владимир Андреевич
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