Identification of Robust Antibiotic Subgroups by Integrating Multi-Species Drug–Drug Interactions

Previous studies have shown that antibiotics can be divided into groups, and drug–drug interactions (DDI) depend on their groups. However, these studies focused on a specific bacteria strain (i.e., Escherichia coli BW25113). Existing datasets often contain noise. Noisy labeled data may have a bad effect on the clustering results. To address this problem, we developed a multi-source information fusion method for integrating DDI information from multiple bacterial strains. Specifically, we calculated drug similarities based on the DDI network of each bacterial strain and then fused these drug similarity matrices to obtain a new fused similarity matrix. The fused similarity matrix was combined with the T-distributed stochastic neighbor embedding algorithm, and hierarchical clustering algorithm can effectively identify antibiotic subgroups. These antibiotic subgroups are strongly correlated with known antibiotic classifications, and group–group interactions are almost monochromatic. In summary, our method provides a promising framework for understanding the mechanism of action of antibiotics and exploring multi-species group–group interactions

Insight into the process of product expulsion in cellobiohydrolase Cel6A from <i>Trichoderma reesei</i> by computational modeling

<p>Glycoside hydrolase cellulase family 6 from <i>Trichoderma reesei</i> (TrCel6A) is an important cellobiohydrolase to hydrolyze cellooligosaccharide into cellobiose. The knowledge of enzymatic mechanisms is critical for improving the conversion efficiency of cellulose into ethanol or other chemicals. However, the process of product expulsion, a key component of enzymatic depolymerization, from TrCel6A has not yet been described in detail. Here, conventional molecular dynamics and steered molecular dynamics (SMD) were applied to study product expulsion from TrCel6A. Tyr103 may be a crucial residue in product expulsion given that it exhibits two different posthydrolytic conformations. In one conformation, Tyr103 rotates to open the −3 subsite. However, Tyr103 does not rotate in the other conformation. Three different routes for product expulsion were proposed on the basis of the two different conformations. The total energy barriers of the three routes were calculated through SMD simulations. The total energy barrier of product expulsion through Route 1, in which Tyr103 does not rotate, was 22.2 kcal·mol⁻¹. The total energy barriers of product expulsion through Routes 2 and 3, in which Tyr103 rotates to open the −3 subsite, were 10.3 and 14.4 kcal·mol⁻¹, respectively. Therefore, Routes 2 and 3 have lower energy barriers than Route 1, and Route 2 is the thermodynamically optimal route for product expulsion. Consequently, the rotation of Tyr103 may be crucial for product release from TrCel6A. Results of this work have potential applications in cellulase engineering.</p