Molecular Mechanism of Interaction between DNA Aptamer and Receptor-Binding Domain of Severe Acute Respiratory Syndrome Coronavirus 2 Variants Revealed by Steered Molecular Dynamics Simulations.

The ongoing SARS-CoV-2 pandemic has underscored the urgent need for versatile and rapidly deployable antiviral strategies. While vaccines have been pivotal in controlling the spread of the virus, the emergence of new variants continues to pose significant challenges to global health. Here, our study focuses on a novel approach to antiviral therapy using DNA aptamers, short oligonucleotides with high specificity and affinity for their targets, as potential inhibitors against the spike protein of SARS-CoV-2 variants Omicron and JN.1. Our research utilizes steered molecular dynamics (SMD) simulations to elucidate the binding mechanisms of a specifically designed DNA aptamer, AM032-4, to the receptor-binding domain (RBD) of the aforementioned variants. The simulations reveal detailed molecular insights into the aptamer-RBD interaction, demonstrating the aptamer's potential to maintain effective binding in the face of rapid viral evolution. Our work not only demonstrates the dynamic interaction between aptamer-RBD for possible antiviral therapy but also introduces a computational method to study aptamer-protein interactions.

Developing Dynamic Structure-Based Pharmacophore and ML-Trained QSAR Models for the Discovery of Novel Resistance-Free RET Tyrosine Kinase Inhibitors Through Extensive MD Trajectories and NRI Analysis.

Activation of RET tyrosine kinase plays a critical role in the pathogenesis of various cancers, including non-small cell lung cancer, papillary thyroid cancers, multiple endocrine neoplasia type 2A and 2B (MEN2A, MEN2B), and familial medullary thyroid cancer. Gene fusions and point mutations in the RET proto-oncogene result in constitutive activation of RET signaling pathways. Consequently, developing effective inhibitors to target RET is of utmost importance. Small molecules have shown promise as inhibitors by binding to the kinase domain of RET and blocking its enzymatic activity. However, the emergence of resistance due to single amino acid changes poses a significant challenge. In this study, a structure-based dynamic pharmacophore-driven approach using E-pharmacophore modeling from molecular dynamics trajectories is proposed to select low-energy favorable hypotheses, and ML-trained QSAR models to predict pIC50 values of compounds. For this aim, extensive small molecule libraries were screened using developed ligand-based models, and potent compounds that are capable of inhibiting RET activation were proposed.

A molecular arm: the molecular bending-unbending mechanism of integrin.

The balance of integrin activation and deactivation regulates its function and mediates cell behaviors. Mechanical force triggers the unbending and activation of integrin. However, how an activated and extended integrin spontaneously bends back is unclear. I performed all-atom molecular dynamics simulations on an integrin or its subunits to reveal the bending-unbending mechanism of integrin. According to the simulations, the integrin structure works like a human arm. The integrin α subunit serves as the bones, while the ß leg serves as the bicep. The integrin extension results in the stretching of the ß leg, and the extended integrin spontaneously bends as a consequence of the contraction of the ß leg. This study provides new insights into the mechanism of how the integrin secures in the bent inactivated state and sheds light on how the integrin could achieve a stable extended state.