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

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.

Network pharmacology and molecular docking combined to investigate the mechanism of duck‐derived active peptides in preventing hypertension

“…During MD simulations, the compactness and rigidity of the protein backbone were assessed by Rg (Su et al ., 2021). IPIIDYEVSITLGDPEALRDLLGEWVPWQ–ACE complex was compact with the Rg value of 0.2–0.4 nm (Fig.…”

Selection of a novel cell-internalizing RNA aptamer specific for CD22 antigen in B cell acute lymphoblastic leukemia

“…Previous molecular docking and molecular dynamics research has focused on understanding aptamer-protein binding after aptamer selection and characterization. 85 , 86 Generally, these techniques have been used for optimizing aptamer stability and specificity for its target protein. 87 , 88 Drawing on strategies that have been applied successfully for other protein-ligand interactions, 60 , 61 , 84 we ranked our aptamer candidates based on the number of predicted H-bonds with the d2–d3 ectodomains of the CD22 protein that includes the epratuzumab epitope.…”

An overview of structural approaches to study therapeutic RNAs

“…Thus, enhanced sampling methods are of strong interest to overcome complicated energy barriers and to efficiently explore a rough free energy surface, simulating events that occur in the range of biologically and thermodynamically relevant RNA motions timescale. Indeed, MD simulation has been recently employed to overcome the high costs and time-consuming SELEX process, as well as to study the interaction mechanism between the aptamer and the target molecule on the atomic scale ( Su et al, 2021 ).…”