The disease of SARS-CoV-2 has caused considerable morbidity and mortality globally. Spike proteins on the surface of SARS-CoV-2 allow it to bind with human cells, leading to infection. Fullerenes and their derivatives are promising SARS-CoV-2 inhibitors and drug-delivery vehicles. In this study, Gaussian accelerated molecular dynamics simulations and the Markov state model were employed to delve into the inhibitory mechanism of Fullerene–linear-polyglycerol-b-amine sulfate (F–LGPS) on spike proteins. During the study, it was discovered that fullerene derivatives can operate at the interface of the receptor-binding domain (RBD) and the N-terminal domain (NTD), keeping structural domains in a downward conformation. It was also observed that F-LGPS demonstrated superior inhibitory effects on the XBB variant in comparison to the wild-type variant. This study yielded invaluable insights for the potential development of efficient therapeutics targeting the spike protein of SARS-CoV-2.

γ-secretase is an intramembrane proteolytic enzyme that is mainly involved in the cleavage and hydrolysis of the amyloid precursor (APP). The catalytic subunit presenilin 1 (PS1) is the catalytic subunit of γ-secretase. Since it was found that PS1 is responsible for Aβ-producing proteolytic activity, which is involved in Alzheimer’s disease, it is believed that reducing the activity of PS1 and preventing or delaying the production of Aβ could help treat Alzheimer’s disease. Consequently, in recent years, researchers have begun investigating the potential clinical efficacy of PS1 inhibitors. Currently, most PS1 inhibitors are only used as a tool to study the structure and function of PS1, and a few inhibitors with a high selectivity have been tested in clinics. Less-selective PS1 inhibitors were found to not only inhibit Aβ production but also inhibit Notch cleavage, which led to serious adverse events. The archaeal presenilin homologue (PSH) is a surrogate protease of presenilin that is useful for agent screening. In this study, we performed 200 ns molecular dynamics simulations (MD) of four systems to explore the conformational changes of different ligands binding to PSH. Our results indicated that the PSH-L679 system formed 3–10 helices in TM4, loosening up TM4 and allowing substrates to enter the catalytic pocket, thereby making it less inhibitory. Additionally, we found that III-31-C can bring TM4 and TM6 closer, resulting in the contraction of the PSH active pocket. Altogether, these results provide the basis for the potential design of newer PS1 inhibitors.

Chitosanase CsnMY002 is a new type of enzyme isolated from Bacillus subtilis that is used to prepare chitosan oligosaccharide. Although mutants G21R and G21K could increase Chitosan yield and thus increase the commercial value of the final product, the mechanism by which this happens is not known. Herein, we used molecular dynamics simulations to explore the conformational changes in CsnMY002 wild type and mutants when they bind substrates. The binding of substrate changed the conformation of protein, stretching and deforming the active and catalytic region. Additionally, the mutants caused different binding modes and catalysis, resulting in different degrees of polymerization of the final Chitooligosaccharide degradation product. Finally, Arg37, Ile145 ~ Gly148 and Trp204 are important catalytic residues of CsnMY002. Our study provides a basis for the engineering of chitosanases.