Study of the binding mechanisms between palytoxin and its aptamer by docking and molecular simulation

Abstract

This paper provides a feasible model for aptamer and its target in molecular structure analysis and interaction mechanism. In this study, modeling and dynamic simulation of ssDNA aptamer (P-18S2) and target (Palytoxin, PTX) were performed separately. Then, the combination mechanism of DNA and PTX were predicted, and docking results showed that PTX can combine steadily in the groove at the top of DNA model trough strong hydrogen-bonds and electrostatic interaction. Therefore, we have further truncated and optimized to P-18S2 by simulating, at the same time, we also confirmed the reliability of simulative results by experimenting. Combining with the experimental and computational results, we provide a more reasonable interpretation for the high affinity and specific binding of P-18S2 and PTX and offer the basis for aptamer development in molecular diagnostics and therapeutic application.\n\nAuthor summaryIn order to further study the complex structure and interaction of P-18S2 and PTX, a series of molecular modeling program were designed, including modeling, traditional dynamics simulation and molecular docking. Modeling results reveal that the structure of P-18S2 is a DNA G-quadruplex. Meanwhile, the 3D structure of PTX with lowest total energy after equilibrium was selected to use for the subsequent simulations. Then, based on the DNA with G-quadruplex structure, the combination model of DNA and PTX were predicted, and docking results showed that PTX can combine steadily in the groove at the top of DNA model trough strong hydrogen-bonds and electrostatic interaction. Futhermore, we compared the affinity of 6 optimized aptamers by computer simulating to primary P-18S2 bind to PTX respectively, the results showed no significant difference. Therefore, we have further truncated and optimized to P-18S2. In addition, this paper further refined research method based on our previous study[17], the instability of the target structure was considered and optimized, and the biological experiments were used to confirm the veracity of the simulative results. Combining with the experimental and computational methods, we obtained a reasonable interpretation for the high affinity and specific binding of P-18S2 and PTX. In summary, we established a feasible model for aptamer and its target in molecular structure analysis and interaction mechanism, and offer the basis for the study of aptamer development in molecular diagnostics and therapeutic application.