Influenza viruses are a major public health threat worldwide. The influenza hemagglutinin (HA) plays an essential role in the virus life cycle. Due to the high conservation of the HA stem region, it has become an especially attractive target for inhibitors for therapeutics. In this study, molecular simulation was applied to study the mechanism of a small molecule inhibitor (MBX2329) of influenza HA. Behaviors of the small molecule under neutral and acidic conditions were investigated, and an interesting dynamic binding mechanism was found. The results suggested that the binding of the inhibitor with HA under neutral conditions facilitates only its intake, while it interacts with HA under acidic conditions using a different mechanism at a new binding site. After a series of experiments, we believe that binding of the inhibitor can prevent the release of HA1 from HA2, further maintaining the rigidity of the HA2 loop and stabilizing the distance between the long helix and short helices. The investigated residues in the new binding site show high conservation, implying that the new binding pocket has the potential to be an effective drug target. The results of this study will provide a theoretical basis for the mechanism of new influenza virus inhibitors.Influenza virus is the causative agent of influenza, an infectious disease which usually leads to symptoms such as high fever, cough, headache, muscle and joint pain, sore throat, nasal discharge, and even a fatal illness similar to pneumonia 1-4 . Influenza viruses are divided into three types, type A, type B and type C, with influenza A virus presenting serious threats to public health worldwide due to its high mutation rate [5][6][7] . At present, two classes of drugs are approved by the Food and Drug Administration for treatment or chemoprophylaxis of influenza: matrix protein 2 (M2) inhibitors amantadine and rimantadine and the neuraminidase (NA) inhibitors (NAIs) oseltamivir and zanamivir 8,9 . However, with the wide use of these drugs, drug-resistant strains have appeared in succession 10 . Therefore, new antiviral targets with novel inhibition mechanism need to be developed.Hemagglutinin (HA), a viral receptor-binding and membrane-fusion glycoprotein involved in the invasion of influenza into host cells, plays an essential role in the life cycle of influenza A virus 3,11 . HA is a trimer of identical subunits, each of which consists of a variable membrane-distal receptor-binding globular domain (HA1) and a more conserved membrane-proximal helix-rich stem structure (HA2) 12 . Under acidic conditions, the residues on the outer surface of HA1 can be protonated easily, which leads to the large gathering of positive charges on the surface of HA 13,14 . With gradually increased charges, disaggregation of HA first occurs as the positive charges repel each other, followed by the entry of water into the interior of the protein causing further structural changes of HA2 13 . In the HA2 subunit, one short and one long α-helical segment are connected by a loop (helix-loo...

Protein tyrosine phosphatase 1B (PTP1B) has become an outstanding target for the treatment of diabetes and obesity. Recent research has demonstrated that some fullerene derivatives serve as a new nanoscale-class of potent inhibitors of PTP1B, but the specific mechanism remains unclear. Several molecular modeling methods (molecular docking, molecular dynamics simulations, and molecular mechanics/generalized Born surface area calculations) were integrated to provide insight into the binding mode and inhibitory mechanism of the new class of fullerene inhibitors. The results reveal that PTP1B with an open WPD loop is more susceptible to the combination with the fullerene inhibitor because of their comparable shapes and sizes. When the WPD loop fluctuates to the open conformation, the inhibitor falls into the active pocket and induces conformational rotation of the WPD loop. This rotation is closely related to the reduction of the catalytic activity of PTP1B. In addition, it is suggested that compound 1, like compound 2, is a competitive inhibitor since it blocks the active site to prevent the binding of the substrate. The high binding affinity of fullerene-based compounds and the transition of the WPD loop, caused by the specific structural property of the hydrophobic fullerene core and the appended polar groups, make these fullerene derivatives efficient competitive inhibitors. The theoretical results provide useful clues for further investigation of the noval inhibitors of PTP1B at the nanoscale.

Optical modulators hold great promise for nonlinear optical and photonic devices. However, current optical modulators are exclusively based on inorganic saturable absorbers such as semiconductor thin films, 2D materials, and plasmonic nanocrystals. Here, nonlinear optical modulation is demonstrated by designing a series of organic semiconducting polymer dots (Pdots) for passive Q‐switching and mode‐locking lasers in the near‐infrared (NIR) region. Combining density functional theory and judicious polymer design, Pdots with large extinction coefficient and broadband absorption are developed which span the entire spectrum from ultraviolet (UV) to NIR region (300 to 2500 nm). The Pdots exhibit strong saturable absorption (β = −1.2 × 10−3 cm W−1) and optical nonlinearity (Imχ(3) = −8.4 × 10−7 esu), which are of orders higher than other nonlinear optical materials such as carbon‐based materials, plasmonic metal nanoparticle, and semiconductor nanocrystals. The Pdot modulators are integrated into the fiber laser systems, and demonstrate passively mode‐locked lasers at 1036, 1038, 1945, 1950 nm and Q‐switched lasers at wavelengths of 1559 and 1957 nm, highlighting the potential of Pdots for advanced nonlinear optical and photonic applications.

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