Interactions of antimicrobial peptides with the targets of their nephrotoxic action. Molecular dynamics simulations

Objectives: The study aimed to investigate the structural aspects of polymyxins nephrotoxicity at the atomic level to promote the more purposeful development of the polymyxin’s derivatives with the lower nephrotoxic action. Materials and methods The molecular dynamics simulations of the complexes of polymyxin B and its derivative NAB7061 (that carries only three positive charges located within the macrocycle) with megalin were done in program package YASARA Structure with explicit water (TIP3P) and ions (0.9% NaCl) in NPT ensemble using the AMRER03 force field. After 10 ns equilibration, each system was simulated at 298 K and pH 7.4 for a 25 ns production phase. Simulations were run twice for each molecular system. Results By molecular dynamics simulations, the possibility was shown for polymyxin to form a stable complex with two neighbor structural domains of megalin in accord with the universal mechanism of binding the cationic ligands by ligand-binding CR repeats of the LDLR-family receptors. It was shown that interactions of megalin with polymyxin are stronger than with its derivative having no positively charged groups outside the macrocycle. The structural prerequisites of these differences were revealed that explain the less nephrotoxicity of such derivatives compared to polymyxin. Conclusions Comparative molecular dynamics simulations of megalin interactions with polymyxin B and its derivative NAB7061 that carries no positive charges located outside the macrocycle revealed the possible structural prerequisites for the lower nephrotoxic action of such polymyxin derivatives. The weakening of polymyxins binding with megalin may become an effective preventive measure against polymyxin-induced nephrotoxicity.