Exploring the most stable aptamer/target molecule complex by the stochastic tunnelling-basin hopping-discrete molecular dynamics method

Chia-Hao Su,Hui-Lung Chen,Yu-Sheng Lin,Shin-Pon Ju,Ta-Feng Tseng,Tai-Ding You

doi:10.1038/s41598-021-90907-y

Abstract

The stochastic tunnelling-basin hopping-discrete molecular dynamics (STUN-BH-DMD) method was applied to the search for the most stable biomolecular complexes in water by using the MARTINI coarse-grained (CG) model. The epithelial cell adhesion molecule (EpCAM, PDB code: 4MZV) was used as an EpCAM adaptor for an EpA (AptEpA) benchmark target molecule. The effects of two adsorption positions on the EpCAM were analysed, and it is found that the AptEpA adsorption configuration located within the EpCAM pocket-like structure is more stable and the energy barrier is lower due to the interaction with water. By the root mean square deviation (RMSD), the configuration of EpCAM in water is more conservative when the AptEpA binds to EpCAM by attaching to the pocket space of the EpCAM dimer. For AptEpA, the root mean square fluctuation (RMSF) analysis result indicates Nucleobase 1 and Nucleobase 2 display higher flexibility during the CGMD simulation. Finally, from the binding energy contour maps and histogram plots of EpCAM and each AptEpA nucleobase, it is clear that the binding energy adsorbed to the pocket-like structure is more continuous than that energy not adsorbed to the pocket-like structure. This study has proposed a new numerical process for applying the STUN-BH-DMD with the CG model, which can reduce computational details and directly find a more stable AptEpA/EpCAM complex in water.

Highlights

The stochastic tunnelling-basin hopping-discrete molecular dynamics (STUN-BH-DMD) method was applied to the search for the most stable biomolecular complexes in water by using the MARTINI coarse-grained (CG) model
In Cunzheng’s s tudy[19], they used the molecular dynamics and molecular docking simulation to investigate the interaction between the DNA aptamer-combined molecular beacon probes (MB) and organophosphorus pesticides
In our previous s tudies[35,36], we have developed and improved a global minimum search method for the all atom model in vacuum, the stochastic tunnelling-basin hopping-discrete molecular dynamics (STUN-BHDMD) method

Summary

Introduction

The stochastic tunnelling-basin hopping-discrete molecular dynamics (STUN-BH-DMD) method was applied to the search for the most stable biomolecular complexes in water by using the MARTINI coarse-grained (CG) model. Among the methods for recognizing the specific cancer cells, single-stranded deoxyribonucleic acid (ssDNA) aptamers with a specific nucleobase sequence can be utilized to identify the particular protein target molecule on a specific cancer cell. After the tumor DNA aptamer attached to the tumor cell, drugs within the silicon nanoparticles could be precisely applied to the tumor cells This method can significantly decrease the drug’s side effects and improve its efficiency. In Cunzheng’s s tudy[19], they used the molecular dynamics and molecular docking simulation to investigate the interaction between the DNA aptamer-combined molecular beacon probes (MB) and organophosphorus pesticides Their simulation results show that the two main factors promoting the stable interaction of aptamer/ organophosphorus pesticides are the intermolecular hydrogen bonding and the Van der Waals energy. The docking simulation results from AutoDock show that the residence time is significantly related to the aptamer’s affinity towards the target molecule

Findings

Discussion

Conclusion