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.

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.

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 β leg serves as the bicep. The integrin extension results in the stretching of the β leg, and the extended integrin spontaneously bends as a consequence of the contraction of the β 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.

SARS-CoV-2 outbreaks worldwide caused COVID-19 pandemic, which is related to several million deaths. In particular, SARS-CoV-2 Spike (S) protein is a major biological target for COVID-19 vaccine design. Unfortunately, recent reports indicated that Spike (S) protein mutations can lead to antibody resistance. However, understanding the process is limited, especially at the atomic scale. The structural change of S protein and neutralizing antibody fragment (FAb) complexes was thus probed using molecular dynamics (MD) simulations. In particular, the backbone RMSD of the 501Y.V2 complex was significantly larger than that of the wild-type one implying a large structural change of the mutation system. Moreover, the mean of Rg, CCS, and SASA are almost the same when compared two complexes, but the distributions of these values are absolutely different. Furthermore, the free energy landscape of the complexes was significantly changed when the 501Y.V2 variant was induced. The binding pose between S protein and FAb was thus altered. The FAb-binding affinity to S protein was thus reduced due to revealing over steered-MD (SMD) simulations. The observation is in good agreement with the respective experiment that the 501Y.V2 SARS-CoV-2 variant can escape from neutralizing antibody (NAb).

The free energy profile of the adenine to guanine transition in the gas and aqueous phases was obtained by applying steered molecular dynamic (SMD) simulations. Three processes were considered to explain the mechanism assisted by water and formic acid molecules. The first process is hydrolytic deamination of adenine, then oxidation of the hypoxanthine previously formed, and finally, the animation from xanthine to guanine. In the gas phase these processes indicate a slow and not spontaneous conversion (ΔG g = 4.07 kcal·mol-1, k = 5.59·10-40 s-1), and a lifetime for guanine of τ = 7.75·10+22 s. The presence of solvent makes the transition more difficult by increasing the reaction energy to 26.90 kcal·mol-1 and decreasing the speed of the process to 1.63·10-55 s-1. However, it decreases the energy of the deamination process to -9.63 kcal·mol-1 and the lifetime of guanine base to τ = 6.85·10+17 s when the surrounding medium used in the transition process is aqueous. The results show that the guanine could participate in genetic mutations based on the lifetimes obtained. Transition states and intermediates structures were analyzed at the molecular dynamic level. This allows to follow the mechanism over time and to calculate thermodynamic and kinetic properties.

The thermodynamics and kinetics of enzymatically assisted reactions of carbon acids were studied theoretically in this work. Quantum electronic (QE) structure calculations and steered molecular dynamics (SMD) simulations were carried out. Three 3-butenal tautomerization reactions that proceed from the β,γ-unsaturated reactant (R) to the α,β-unsaturated carbon acid product (P) and occur in two elementary steps through an intermediate (I) were studied, ignoring or including the surrounding aqueous medium in the calculations. The Gibbs free energies of activation of the R ⇆ I enolization and I ⇆ P ketonization steps were found to decrease considerably when residues simulating enzymes were introduced into these processes. Although the processes became slightly more favorable thermodynamically when the solution was included in the simulations, they became less favorable kinetically. The results from SMD simulations of these reactions were qualitatively consistent with the values we obtained using QE as well as those found by other authors in similar studies. Our simulations also allowed us to perform a detailed study of these reactions in solution.

The zoonotic disease brucellosis, a chronic condition in humans affecting renal and cardiac systems and causing osteoarthritis, is caused by Brucella, a genus of Gram-negative, facultative, intracellular pathogens. The mode of transmission and the virulence of the pathogens are still enigmatic. Transcription regulatory elements, such as rho proteins, play an important role in the termination of transcription and/or the selection of genes in Brucella. Adverse effects of the transcription inhibitors play a key role in the non-successive transcription challenges faced by the pathogens. In the investigation presented here, we computationally predicted the transcription termination factor rho (TtFRho) inhibitors against Brucella melitensis 16M via a structure-based method. In view the unknown nature of its crystal structure, we constructed a robust three-dimensional homology model of TtFRho\'s structure by comparative modeling with the crystal structure of the Escherichia coli TtFRho (Protein Data Bank ID: 1PVO) as a template in MODELLER (v 9.10). The modeled structure was optimized by applying a molecular dynamics simulation for 2 ns with the CHARMM (Chemistry at HARvard Macromolecular Mechanics) 27 force field in NAMD (NAnoscale Molecular Dynamics program; v 2.9) and then evaluated by calculating the stereochemical quality of the protein. The flexible docking for the interaction phenomenon of the template consists of ligand-related inhibitor molecules from the ZINC (ZINC Is Not Commercial) database using a structure-based virtual screening strategy against minimized TtFRho. Docking simulations revealed two inhibitors compounds - ZINC24934545 and ZINC72319544 - that showed high binding affinity among 2,829 drug analogs that bind with key active-site residues; these residues are considered for protein-ligand binding and unbinding pathways via steered molecular dynamics simulations. Arg215 in the model plays an important role in the stability of the protein-ligand complex via a hydrogen bonding interaction by aromatic-π contacts, and the ADMET (absorption, distribution, metabolism, and excretion) analysis of best leads indicate nontoxic in nature with good potential for drug development.