Molecular dynamics study of interactions of polymyxin B3 and its ALA-mutants with lipopolysaccharide
Keywords:
polymyxin, lipopolysaccharide, lipid A, docking, molecular modeling.Abstract
Introduction. Emergence of nosocomial bacterial pathogens (especially Gram-negative bacteria) with multiple resistance against almost all available antibiotics is a growing medical problem. No novel drugs targeting multidrug-resistant Gram-negative bacteria have been developed in recent years. In this context, there has been greatly renewed interest to cyclic lipodecapeptides polymyxins. Polymyxins exhibit rapid bactericidal activity, they are specific and highly potent against Gram-negative bacteria, but have potential nephrotoxic side effects. So polymyxins are attractive lead compounds to develop analogues with improved microbiological, pharmacological and toxicological properties. A detailed knowledge of the molecular mechanisms of polymyxin interactions with its cell targets is a prerequisite for the purposeful improvement of its therapeutic properties. The primary cell target of a polymyxin is a lipopolysaccharide (LPS)in the outer membrane of Gram-negative bacteria. The binding site of polymyxin on LPS has been supposed to be Kdo2-lipid A fragment. Methods.For all molecular modeling and molecular dynamics simulation experiments the YASARA suite of programs was used. Complex of antimicrobial peptide polymyxin В3 (PmB3) with Kdo2-lipid A portion of E. coli lipopolysaccharide was constructed by rigid docking with flexible side chains of the peptide. By alanine scanning of polymyxin В3 bound to LPS followed by simulated annealing minimization of the complexes in explicit water environment, the molecular aspects ofPmB3-LPS binding have beenstudied by 20 ns molecular dynamics simulations at 298 K and pH 7.0. The AMBER03 force field was used with a 1.05 nm force cutoff. To treat long range electrostatic interactions the Particle Mesh Ewald algorithm was used. Results. Ala-mutations of polymyxin’s residues Dab1, Dab3, Dab5, Dab8 and Dab9 in the PmB3-LPScomplex caused sustained structural changes resulting in the notable loss in stability of LPS complexes with Ala-mutants of PmB3. The mutations disturbed the characteristic hydrogen-bond network of PmB3-LPScomplex. Ala-mutations of Dab1, Dab8 and Dab9 amino acid residues of PmB3destabilized PmB3-LPS complex to a greater extent: the values of binding energy for these mutants showed increase and large-amplitude irregular fluctuations.
Conclusions. Hydrogen bonding of polymyxin B with the lipopolysaccharide is an important factor of the stability of PmB3-LPScomplex. Detailed knowledge of the peculiarities of molecular interactions of polymyxins with its primary target on the outer membrane of Gram-negative bacteria is a prerequisite of a purposeful design of novel polymyxin-like lipopeptides.
References
Nicasio, A.M. The current state of multidrug-resistant gram-negative bacilli in North America. Insight from the Society of Infectious Diseases Pharmacists [Text] / A. M. Nicasio, J. L. Kuti, D. P. Nicolau // Pharmacotherapy. – 2008. – Vol. 28, N 2. – P. 235-249.
Yoneyama, H. Antibiotic resistance in bacteria and its future novel antibiotic development [Text] / H. Yoneyama, R. Katsumata R. // Biosci. Biotechnol. Biochem. – 2006. – Vol. 70, N 5. – P. 1060-1075.
Butler, M. S. Antibiotics in the clinical pipeline in 2011 [Text] / M. S. Butler, A. Cooper // J. Antibiot. – 2011. – Vol. 64, N 6. – P. 413-425.
Vlieghe, P. Synthetic therapeutic peptides: science and market [Text] / P. Vlieghe, V. Lisowski, J. Martinez, M. Khrestchatisky // Drug Discov. Today. – 2010. – Vol. 15, N1/2. – P. 40-56.
Velkov, T. Pharmacology of polymixins: new insights into “old” class of antibiotics [Text] / T. Velkov, K. D. Roberts, R. L. Nation, P. E. Thompson, J. Li // Future Microbiol. 2013. – Vol. 8, N 6. – P. 711-724.
Landman, D. Polymyxin revisited [Text] / D. Landman, C. Georgescu, A. M. Martin, J. Quale // Clin. Microbiol. Reviews. – 2008- Vol. 21, N 3. – P. 449-465.
Kwa A. I. Polymyxins: a critical review of the current status including recent developments [Text] / A. I. Kwa, V. H. Tam, M. E. Falagas // Ann. Acad. Med. Singapore. – 2008. – Vol. 37, N 10. – P. 870-883.
Hancock, R. E. W. Role of the membranes in the activities of antimicrobial peptides [Text] / R. E. W. Hancock, A. Rozek // FEMS Microbiol. Lett. – 2002. – Vol. 206, N 2. – P. 143-149.
Gales, A. C. Contemporary activity of colistin and polymyxin B against of Gram-negative pathogens: results from the SENTRY antimicrobial surveillance programme (2006-2009) [Text] / A. C. Gales, R. N. Jones, H. S. Sader // J. Antimicrob. Chemother. – 2011. – Vol. 66, N 9. – P. 2070-2074.
Velkov, T. Structure-activity relationships of polymyxin antibiotics [Text] / T. Velkov, P. E. Thompson, R. L. Nation, J. Li // J. Med. Chem. – 2010/ - Vol. 53, N 5. – P. 1898–1916.
Powers, J.-P. S. The relationship between peptide structure and antibacterial activity [Text] / J.-P. S. Powers, R. E. W. Hancock // Peptides. – 2003. – Vol. 24, N11. – P. 1681–1691.
Hancock, R. E. W. Peptide antibiotics [Text] / R. E. W. Hancock, D. S. Chapple // Antimicrob. Agents Chemother. – 1999. – Vol. 43, N 6. – P. 1317-1323.
Nikaido, H. Molecular basis of bacterial outer membrane permeability revisited [Text] / H. Nikaido // Microbiol. Molec. Biol. Rev. – 2003. – Vol. 67, N 4. – P. 593-656.
Ferguson, A. D. A conserved structural motif for lipopolysaccharide recognition by procaryotic and eucaryotic proteins [Text] / A. D. Ferguson, W. Welte, E. Hofmann, B. Lindner, O. Holst, J. W. Coulton, K. Diederichs // Structure. – 2000. – Vol. 8, N6. – P. 585-592.
Hoess, A. Crystal structure of an endotoxin-neutralizing protein from the horseshoe crab, Limulus anti-LPS factor, at 1.5 Å resolution [Text] / A. Hoess, S. Watson, G. R. Siber, R. Liddington // EMBO J. – 1993. – Vol. 12, N9. – P. 3351-3356.
Japelj, B. Structural origin of endotoxin neutralizing and antimicrobial activity of a lactoferrin-based peptide [Text] / B. Japelj, P. Pristovček, A. Majerle, R. Jerala // J. Biol. Chem. 2005. – Vol. 280, N 17. – P. 16955-16961.
Pristovček, P. Solution structure of polymyxins B and E and effect of binding to lipopolysaccharide: an NMR and molecular dynamics study [Text] / P. Pristovček, J. Kidrič // J. Med. Chem. – 1999. – Vol. 42, N 22. – P. 4604-4613.
Pristovček, P. The structure of endotoxin-neutralizing peptides bound to LPS [Text[ / P. Pristovček, J. Kidrič // Drug discovery and design: medical aspects. Eds J. Matsoukas and T. Mavromoustacos. Amsterdam: IOS Press. – 2002. – Vol. 55. – P. 162-166.
Bhattacharjya, S. Polymyxin B nonapeptide: conformations in water and in the lipopolysaccharide-bound state determined by two-dimensional NMR and molecular dynamics [Text] / S. Bhattacharjya, S. A. David, V. I. Mathan, P. Balaram // Bioploymers. – 1997. - Vol. 41, N 3. – P. 251-265.
Mares, J. Interactions of lipopolysaccharide and polymyxin studied by NMR spectroscopy [Text] / J. Mares, S. Kumaran, M. Gobbo, O. Zerbe // J. Biol. Chem. – 2009. – Vol. 284, N 17. – P. 11498-11506.
Kanazawa, K. Contribution of each amino acid residue in polymyxin B3 to antimicrobial and lipopolysaccharide binding activity [Text] / K. Kanazawa, Y. Sato, K. Ohki, K. Okimura, Y. Uchida, M. Shindo, N. Sakura N. // Chem. Pharm. Bull. – 2009. – Vol. 57, N 3. – P. 240-244.
Krieger, E. Making optimal use of empirical energy functions: force field parameterization in crystal space [Text] / E. Krieger, T. Darden, S. Nabuurs, A. Finkelstein, G. Vriend // Proteins. – 2004. – Vol. 57, N 4. – P. 678-683.
Krieger, E. Fast empirical pKa prediction by Ewald summation [Text] / E. Krieger, J. E. Nielsen, C. A. Spronk, G. Vriend // J. Mol. Graph. Model. – 2006. – Vol. 25, N 4. – P. 481-486.
Duan, Y. A Point-Charge Force Field for Molecular Mechanics Simulations of Proteins [Text] / Y. Duan, C. Wu, S. Chowdhury, M. C. Lee, G. Xiong, W. Zhang, R. Yang, P. Cieplak, R. Luo, T. Lee // J. Comput. Chem. – 2003. – Vol. 24, N 16. – P. 1999-2012.
Essman, U. A smooth particle mesh Ewald method [Text] / U. Essman, L. Perera, M. L. Berkowitz, T. Darden, H. Lee, L. G. Pedersen // J. Chem. Phys. B. – 1995. – Vol. 103, N 19. – P. 8577-8593.
Trott, O. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading [Text] / O. Trott // J. Comput. Chem. – 2010. – Vol. 31, N 2. – P. 455-461.
Wang, J. Development and testing of a general amber force field [Text] / J. Wang, R. M. Wolf, J. W. Caldwell, P. A. Kollman, D. A. Case // J. Comput. Chem. – 2004. – Vol. 25, N 9. – P. 1157-1174.
Jakalian, A. Fast, efficient generation of high-quality atomic charges. AM1-BCC model: II. Parameterization and validation [Text] / A. Jakalian, D. B. Jack, C. I. Bayly // J. Comput. Chem. – 2002. – Vol. 23, N 15. – P. 1623-1641.
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