Characterizing the Binding Sites for GK Domain of DLG1 and DLG4 via Molecular Dynamics Simulation

Abstract

Discs-large (DLG) is a member that belongs to the membrane-associated guanylate kinase (MAGUK) family. The GK domain of DLGs has evolved into a protein-protein interaction module that could bind with kinds of proteins to regulate diverse cellular functions. Previous reports have demonstrated the GK domain of DLGs functioned as a phosphor-peptide-binding module by resolving the crystal structures. Here we investigated into the interactions of DLG1 and DLG4 with their reported phosphor-peptides by molecular dynamics simulations. Post-dynamics analysis showed that DLG1/4 formed extensive interactions with phosphorylated ligands, including hydrophobic and hydrogen bonding interactions. Among them, the highly conserved residues among the DLGs in phosphor-site and β5 sheet were crucial for the binding according to the energy decomposition calculations. Additionally, the binding interactions between DLG4 and reported unphosphorylated peptides including MAP1A and designed GK inhibitory (GKI-QSF) peptides were analyzed. We found the key residues that played important roles in DLG4/unphosphorylated peptide systems were very similar as in DLG4/phosphor-peptide systems. Moreover, the molecular dynamic simulation for the complex of DLG1 and GKI-QSF was carried out and predicted that the GKI-QSF could bind with DLG1 with similar Kd value compared to DLG4/GKI-QSF, which was verified by using ITC assay (Kd = 1.20 ± 0.29 µM). Our study might be helpful for the better understanding of the structural and biological function of DLGs GK domain and encourage the discovery of new binders.

Identification of Potential Flavonoid Inhibitors of the SARS-CoV-2 Main Protease 6YNQ: A Molecular Docking Study

“…Taken together, this suggests that it exhibits the strongest and most stable binding. This result is in agreement with previously published data that suggest that rutin (docking score: − 9.16 kcal/mol) is the most potent inhibitor for 6LU7 [ 31 ] . Other researchers have also reported that rutin is an effective inhibitor of various targets of the SARS-CoV-2 proteases [ 32 ] .…”

Transport mechanisms of SARS-CoV-E viroporin in calcium solutions: Lipid-dependent Anomalous Mole Fraction Effect and regulation of pore conductance

“…The Covid-19 pandemic has sparked intense research into the structure of the SARS-CoV-2 coronavirus aimed to understand its mechanism of infection and hamper its virulence [ [1] , [2] , [3] ]. The SARS-CoV-2 RNA genome encodes several membrane proteins, one of which, the envelope protein E, is a small hydrophobic protein with ion channel activity localized at the endoplasmic reticulum-Golgi intermediate compartment (ERGIC).…”

“…The SARS-CoV-2 RNA genome encodes several membrane proteins, one of which, the envelope protein E, is a small hydrophobic protein with ion channel activity localized at the endoplasmic reticulum-Golgi intermediate compartment (ERGIC). Importantly, the E protein of SARS-CoV-2 shares a high degree of similarity with the severe acute respiratory syndrome coronavirus (SARS-CoV) E protein studied here and their transmembrane domains – responsible for the ion channel activity – have identical amino acid sequences [ 1 , 2 , 4 ]. In addition, recent in silico studies predict analogous ion channel activity of both proteins [ 1 ].…”

“…Importantly, the E protein of SARS-CoV-2 shares a high degree of similarity with the severe acute respiratory syndrome coronavirus (SARS-CoV) E protein studied here and their transmembrane domains – responsible for the ion channel activity – have identical amino acid sequences [ 1 , 2 , 4 ]. In addition, recent in silico studies predict analogous ion channel activity of both proteins [ 1 ]. Viroporins have been associated to viral replication and pathogenesis [ 5 ].…”

The epigenetic implication in coronavirus infection and therapy

“…Novel strategies employing small interfering RNAs (siRNAs), microRNAs (miRNAs), and locked nucleic acid antisense oligonucleotides (LNA) or GapmeRs, targeting, for instance, the 5′URT or regions of the Spike molecule, represent potential therapeutic tools for both prophylaxis and therapy of COVID-19 [ 101 – 103 ]. Indeed, the design of antisense oligonucleotides, such as Miravirsen, under investigation for HCV treatment, could be used to inhibit viral replication by scavenging miRNAs that are involved in the process [ 104 , 105 ]. These studies suggest that RNA-based drugs could be optimized and employed to interfere with SARS-CoV-2 replication and transcription.…”