抗菌肽Magainin和Indolicidin对革兰氏阴性菌和阳性菌膜的作用机制

Mechanism of Action of Antimicrobial Peptides Magainin and Indolicidin on Gram-negative and Gram-positive Bacterial Membranes

摘要

采用分子动力学模拟对比研究了抗菌肽Magainin和Indolicidin分别与革兰氏阴性菌和阳性菌膜的相互作用机制. 统计分析了两种肽的结构变化、吸附过程、对膜结构的扰动及其与膜的相互作用. 结果表明, Magainin在水相中螺旋结构较不稳定, 但在膜环境中可重新形成稳定的螺旋结构, 且在革兰氏阴性菌膜上表现出更强的结合能力和更显著的膜扰动效应, 说明其对革兰氏阴性菌膜具有更高的选择性. 相比之下, Indolicidin始终保持柔性的无规卷曲结构, 通过快速吸附与膜表面稳定结合, 其作用机制以静电吸引和疏水作用协同为主, 但对革兰氏阴性菌膜和阳性菌膜的扰动均较小. 对比研究结果为理解Magainin对革兰氏阴性菌的选择性和Indolicidin的广谱性提供了理论依据.

Abstract

Molecular dynamics simulations were employed to comparatively investigate the interaction mechanisms of the antimicrobial peptides Magainin and Indolicidin with the cell membranes of Gram-negative and Gram-positive bacteria, respectively. Structural changes, adsorption process, membrane perturbations, and peptide-membrane interactions of both peptides were systematically analyzed. The results demonstrate that Magainin, which exhibits an unstable helical structure in an aqueous environment, forms a stable helix upon binding to membranes. Moreover, it shows stronger binding ability and more significant disruption on the membrane of Gram-negative bacteria, indicating its higher selectivity for this type of bacteria. In contrast, Indolicidin maintains a flexible random coil structure, enabling rapid adsorption and stable binding to the membrane surface primarily through synergistic electrostatic attraction and hydrophobic interactions. However, it causes relatively minor perturbation to both types of bacterial membranes. This comparative study provides a theoretical basis for understanding the selectivity of Magainin for Gram-negative bacteria and the broad-spectrum activity of Indolicidin.

关键词

Magainin / Indolicidin / 革兰氏阴性菌膜 / 革兰氏阳性菌膜

Key words

Magainin / Indolicidin / Gram-negative bacterial membrane / Gram-positive bacterial membrane

参考文献

[1] Szymczak P., Zarzecki W., Wang J. J., Duan Y. Q., Wang J., Coelho L. P., Fuente-Nunez C., Szczurek E., Acc. Chem. Res., 2025, 58(12), 1831-1846

[2] He M. Y., Jiang Y. Q., Yang Y., Gong K. P., Jiang X. P., Tian Y., J. Phys. Chem. B, 2025, 129(7), 1956-1965

[3] Ahmad N. A., Ho J., J. Chem. Inf. Model., 2025, 65(1), 417-426

[4] Vega S. M., Booth V., Rowley C. N., J. Phys. Chem. B, 2022, 126(29), 5473-5480

[5] Fitz A. R., Klimov D. K., Lockhart C., J. Chem. Inf. Model., 2025, 65(17), 9251-9260

[6] Zasloff M., Nature, 2002, 415(6870), 389-395

[7] Subbalakshmi C., Sitaram N., FEMS Microbiol. Lett., 1998, 160(1), 91-96

[8] Jackel E., Lazzeri G., Covino R., J. Phys. Chem. B, 2025, 129(5), 1586-1596

[9] Benjamin A. B., Moule M. G., Didwania M. K., Hardy J., Saenkham-Huntsinger P., Sule P., Nielsen J. E., Lin J. S., Contag C. H., Barron A. E., Cirillo J. D., Microbiol. Spectr., 2022, 10(3), e0053422

[10] Wang H. P., Liu X. Y., Cai W. S., Shao X. G., Biomacromolecules, 2025, 26(11), 7838-7851

[11] Miao M. Y., Guo Y. C., Shao X. G., Cai W. S., Chem. J. Chinese Universities, 2021, 42(10), 3116-3124

[12] (妙孟姚, 郭一畅, 邵学广, 蔡文生. 高等学校化学学报, 2021, 42(10), 3116-3124)

[13] Cui S. L., Zhang W. J., Shao X. G., Cai W. S., Chem. J. Chinese Universities, 2022, 43(3), 20210838

[14] (崔韶丽, 张维佳, 邵学广, 蔡文生. 高等学校化学学报, 2022, 43(3), 20210838)

[15] Su L. L., Shao X. G., Cai W. S., Chem. J. Chinese Universities, 2023, 44(4), 20220745

[16] (粟李醴, 邵学广, 蔡文生. 高等学校化学学报, 2023, 44(4), 20220745)

[17] Tian C. S., Liu X. Y., Hao Y. L., Fu H. H., Shao X. G., Cai W. S., J. Phys. Chem. B, 2025, 129(5), 1453-1461

[18] Hao Y. L., Liu X. Y., Fu H. H., Shao X. G., Cai W. S., Bioinformatics, 2024, 40(8), btae497

[19] Tian C. S., Hao Y. L., Fu H. H., Shao X. G., Cai W. S., J. Chem. Inf. Model., 2025, 65(18), 9566-9575

[20] Rivel T., Biriukov D., Kabelka I., Vácha R., J. Chem. Inf. Model., 2025, 65(2), 908-920

[21] Andreev K., Martynowycz M. W., Ivankin A., Huang M. L., Kuzmenko I., Meron M., Lin B., Kirshenbaum K., Gidalevitz D., Langmuir, 2016, 32(48), 12905-12913

[22] Hayouka Z., Mortenson D. E., Kreitler D. F., Weisblum B., Forest K. T., Gellman S. H., J. Am. Chem. Soc., 2013, 135(42), 15738-15741

[23] Rozek A., Friedrich C. L., Hancock R. E., Biochemistry, 2000, 39(51), 15765-15774

[24] Jo S., Kim T., Iyer V. G., Im W., J. Comput. Chem., 2008, 29(11), 1859-1865

[25] Sharma P., Vaiwala R., Gopinath A. K., Chockalingam R., Ayappa K. G., Langmuir, 2024, 40(15), 7791-7811

[26] Yao H., Hong M., J. Am. Chem. Soc., 2014, 136(6), 2611-2624

[27] Phillips J. C., Hardy D. J., Maia J. D. C., Stone J. E., Ribeiro J. V., Bernardi R. C., Buch R., Fiorin G., Hénin J., Jiang W., McGreevy R., Melo M. C. R., Radak B. K., Skeel R. D., Singharoy A., Wang Y., Roux B., Aksimentiev A., Luthey-Schulten Z., Kalé L. V., Schulten K., Chipot C., Tajkhorshid E., J. Chem. Phys., 2020, 153(4), 044130

[28] Huang J., Rauscher S., Nawrocki G., Ran T., Feig M., de Groot B. L., Grubmüller H., MacKerell A. D., Nat. Methods, 2017, 14(1), 71-73

[29] Jorgensen W. L., Chandrasekhar J., Madura J. D., Impey R. W., Klein M. L., J. Chem. Phys., 1983, 79(2), 926-935

[30] Feller S. E., Zhang Y., Pastor R. W., Brooks B. R., J. Chem. Phys., 1995, 103(11), 4613-4621

[31] Ulmschneider J. P., Smith J. C., White S. H., Ulmschneider M. B., J. Am. Chem. Soc., 2011, 133(39), 15487-15495

[32] Ulmschneider M. B., Ulmschneider J. P., Schiller N., Wallace B. A., Von Heijne G., White S. H., Nat. Commun., 2014, 5, 4863

[33] Chen C. H., Starr C. G., Troendle E., Wiedman G., Wimley W. C., Ulmschneider J. P., Ulmschneider M. B., J. Am. Chem. Soc., 2019, 141(12), 4839-4848

[34] Hess B., Bekker H., Berendsen H. J. C., Fraaije J. G. E. M., J. Comput. Chem., 1997, 18(12), 1463-1472

[35] Essmann U., Perera L., Berkowitz M. L., Darden T., Lee H., Pedersen L. G., J. Chem. Phys., 1995, 103(19), 8577-8593

[36] Humphrey W., Dalke A., Schulten K., J. Mol. Graph., 1996, 14(1), 33-38

[37] Kumar A., Mishra B., Konar A. D., Mylonakis E., Basu A., J. Phys. Chem. B, 2024, 128(25), 6049-6058

[38] Volovik M. V., Batishchev O. V., Biomolecules, 2024, 14(9), 1118

[39] Fojan P., Gurevich L., Methods Mol. Biol., 2017, 1548, 201-215

[40] Liu L., Shi Z. H., Tong M. Q., Fang Y. Q., Yang D. Y., Yu J. F., Cao Z. X., J. Chem. Inf. Model., 2025, 65(5), 2623-2635

[41] Jaradat D. M. M., Saleh K. K. Y., Za'arir B. H. M., Arafat T., Alzoubi K. H., Al-Taweel S. A., Mallah E., Haddad M. A., Haimur B. A. K., Int. J. Pept. Res. Ther., 2019, 25(3), 1095-1102

[42] Gupta S., Abhishek , Shrivastava S., Singh R. J., Gogoi P., Kumar B., Int. J. Pept. Res. Ther., 2021, 27(2), 1111-1119

[43] Vergis J., Malik S. S., Pathak R., Kumar M., Ramanjaneya S., Kurkure N. V., Barbuddhe S. B., Rawool D. B., Front. Microbiol., 2019, 10, 2723

[44] Nguyen L. T., Haney E. F., Vogel H. J., Trends Biotechnol., 2011, 29(9), 464-472

[45] Talandashti R., Mehrnejad F., Rostamipour K., Doustdar F., Lavasanifar A., J. Phys. Chem. B, 2021, 125(26), 7163-7176

[46] Ma W. D., Sun S. Q., Li W. W., Zhang Z. H., Lin Z., Xia Y., Yuan B., Yang K., Langmuir, 2020, 36(26), 7190-7199

基金资助

国家自然科学基金(22373051)