An Attempt of Seeking Favorable Binding Free Energy Prediction Schemes Considering the Entropic Effect on Fis-DNA Binding

Protein–DNA binding mechanisms in a complex manner are essential for understanding many biological processes. Over the past decades, numerous experiments and calculations have analyzed the specificity of protein–DNA binding. However, the accuracy of binding free energy prediction for multi-base DNA systems still needs to be improved. Fis is a DNA-binding protein that regulates various transcription and recombination reactions. In the present work, we tested several methods of predict binding free energy based on this system to find a favorable prediction scheme and explore the binding mechanism of Fis protein and DNA. Two solvent models (explicit and implicit solvent models) were chosen for the dynamics process, and the predicted binding free energy was more accurate under the explicit solvent model. When different Poisson–Boltzmann/Generalized Born (PB/GB) models were tested for DNA force fields (BSC1 and OL15), it was found that the binding free energy predicted by the selected OL15 force field performed better and the correlation between predicted and experimental values was improved with the increasing interior dielectric constant (Dk). Finally, using Dk = 8, the GBOBC1 model combined with interaction entropy (IE), which was calculated for entropic contribution (GBOBC1_IE_8), was screened out for the binding free energy prediction and analysis of the Fis–DNA system, and the validity of the method was further verified by testing the Cren7–DNA system. By performing conformational analysis of the minor groove, it was found that mutation of the DNA central sequence A/T to C/G and deletion of the guanine 2-amino group would change the minor groove width and thus affect the formation of the major groove, altering the interaction and atomic contact between the protein and the major groove, thus changing the binding affinity of Fis and DNA. Hopefully, the series of tests in this work can shed some light on the related studies of protein and DNA systems

Molecular Mechanism of the Non-Covalent Orally Targeted SARS-CoV‑2 M^pro Inhibitor S‑217622 and Computational Assessment of Its Effectiveness against Mainstream Variants

Convenient and efficient therapeutic agents are urgently needed to block the continued spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, the mechanism for the novel orally targeted SARS-CoV-2 main protease (Mpro) inhibitor S-217622 is revealed through a molecular dynamics simulation. The difference in the movement modes of the S-217622–Mpro complex and apo-Mpro suggested S-217622 could inhibit the motility intensity of Mpro, thus maintaining their stable binding. Subsequent energy calculations showed that the P2 pharmacophore possessed the highest energy contribution among the three pharmacophores of S-217622. Additionally, hot-spot residues H41, M165, C145, E166, and H163 have strong interactions with S-217622. To further investigate the resistance of S-217622 to six mainstream variants, the binding modes of S-217622 with these variants were elucidated. The subtle differences in energy compared to that of the wild type implied that the binding patterns of these systems were similar, and S-217622 still inhibited these variants. We hope this work will provide theoretical insights for optimizing novel targeted Mpro drugs

Immune Escape Mechanisms of SARS-CoV‑2 Delta and Omicron Variants against Two Monoclonal Antibodies That Received Emergency Use Authorization

Multiple-site mutated SARS-CoV-2 Delta and Omicron variants may trigger immune escape against existing monoclonal antibodies. Here, molecular dynamics simulations combined with the interaction entropy method reveal the escape mechanism of Delta/Omicron variants to Bamlanivimab/Etesevimab. The result shows the significantly reduced binding affinity of the Omicron variant for both antibodies, due to the introduction of positively charged residues that greatly weaken their electrostatic interactions. Meanwhile, significant structural deflection induces fewer atomic contacts and an unstable binding mode. As for the Delta variant, the reduced binding affinity for Bamlanivimab is owing to the alienation of the receptor-binding domain to the main part of this antibody, and the binding mode of the Delta variant to Etesevimab is similar to that of the wild type, suggesting that Etesevimab could still be effective against the Delta variant. We hope this work will provide timely theoretical insights into developing antibodies to prevalent and possible future variants of SARS-CoV-2