Link prediction of viral spike proteins and cell receptors using structural perturbation method

Many protein receptors for animal and human viruses have been discovered in decades of studies. The main determinant of virus entry is the binding of the viral spike protein to host cell receptors, which mediates membrane fusion.In this work, a bilayer network is constructed by integrating the similarity network of the viral spike proteins, the similarity network of host receptors, and the association network between viruses and receptors. The structural perturbation method (SPM) is used to predict possible emerging infection of a virus in potential new host organisms. The reliability of this method is based on the hypothesis that the major barrier to virus infection is the differences in the compatibility of spike proteins and cell receptors, which is determined by the amino acid sequences among species.

Link prediction of viral spike proteins and cell receptors using structural perturbation method

Many protein receptors for animal and human viruses have been discovered in decades of studies. The main determinant of virus entry is the binding of the viral spike protein to host cell receptors, which mediates membrane fusion. In this work, a bilayer network is constructed by integrating the similarity network of the viral spike proteins, the similarity network of host receptors, and the association network between viruses and receptors. The structural perturbation method (SPM) is used to predict possible emerging infection of a virus in potential new host organisms. The reliability of this method is based on the hypothesis that the major barrier to virus infection is the differences in the compatibility of spike proteins and cell receptors, which is determined by the amino acid sequences among species.

SPMLMI: predicting lncRNA–miRNA interactions in humans using a structural perturbation method

Long non-coding RNA (lncRNA)–microRNA (miRNA) interactions are quickly emerging as important mechanisms underlying the functions of non-coding RNAs. Accordingly, predicting lncRNA–miRNA interactions provides an important basis for understanding the mechanisms of action of ncRNAs. However, the accuracy of the established prediction methods is still limited. In this study, we used structural consistency to measure the predictability of interactive links based on a bilayer network by integrating information for known lncRNA–miRNA interactions, an lncRNA similarity network, and an miRNA similarity network. In particular, by using the structural perturbation method, we proposed a framework called SPMLMI to predict potential lncRNA–miRNA interactions based on the bilayer network. We found that the structural consistency of the bilayer network was higher than that of any single network, supporting the utility of bilayer network construction for the prediction of lncRNA–miRNA interactions. Applying SPMLMI to three real datasets, we obtained areas under the curves of 0.9512 ± 0.0034, 0.8767 ± 0.0033, and 0.8653 ± 0.0021 based on 5-fold cross-validation, suggesting good model performance. In addition, the generalizability of SPMLMI was better than that of the previously established methods. Case studies of two lncRNAs (i.e., SNHG14 and MALAT1) further demonstrated the feasibility and effectiveness of the method. Therefore, SPMLMI is a feasible approach to identify novel lncRNA–miRNA interactions underlying complex biological processes.

A Bioinformatics Study of Structural Perturbation of 3CL-Protease and the HR2-Domain of SARS-CoV-2 Induced by Synergistic Interaction with Ivermectins

The pandemic caused by SARS-CoV-2 forces drug research to combat it. Ivermectin, an FDA approved antiparasitic drug formulated as a mixture 80:20 of the equipotent homologous 22,23 dihydro ivermectin (B1_a and B1_b), which is known to inhibit SARS-CoV-2 in vitro with a mechanism of action to be defined. It draws attention powerfully that the energetic and structural perturbation that this drug induces by binding on SARS-COV-2 proteins of importance for its proliferation is ill unknown. Hence what we do an exhaustive computational biophysics study to discriminate the best docking of ivermectins to viral proteins and, subsequently, to analyze possible structural alterations with molecular dynamics. The results suggested that ivermectins are capable of docking to the superficial and internal pocket of the 3CL-protease and the HR2-domain, inducing unfolding/folding that change the native conformation in these proteins. In particular, ivermectin binds to the 3CL protease and leads this protein to an unfolded state, whereas the HR2-domain to a more compact conformation in comparison to the native state by refolding when the drug binding to this protein. The results obtained suggest a possible synergistic inhibitory against SARS-COV-2 owing to each role of ivermectins when favorably binding to these viral proteins. Given the importance of the results obtained about this new mechanism of action of ivermectin on SARS-CoV-2, experimental studies are needed that corroborate this proposal.

Structure Basis of Cav1.1 Modulation by Dihydropyridine Compounds

Abstract1,4-Dihydropyridines (DHP), the most commonly used antihypertensives, function by inhibiting the L-type voltage-gated Ca2+ (Cav) channels. DHP compounds exhibit chirality-specific antagonistic or agonistic effects. Recent structural elucidation of rabbit Cav1.1 bound to an achiral drug nifedipine reveals the general binding mode for DHP drugs, but the molecular basis for chiral specificity remains elusive. Here, we report five cryo-EM structures of nanodisc-embedded Cav1.1 in the presence of the bestselling drug amlodipine, a DHP antagonist (R)-(+)-Bay K8644, and a titration of its agonistic enantiomer (S)-(-)-Bay K8644 at resolutions of 2.9-3.4 Å. The amlodipine-bound structure reveals the molecular basis for the high efficacy of the drug. All structures with the addition of the Bay K8644 enantiomers exhibit similar inactivated conformations, suggesting that the agonistic effect of (S)-(-)-Bay K8644 might be transient. The similarity of these structures to that obtained in detergent micelles alleviates the concerns about potential structural perturbation by detergents.