Biology subjects

Achilonu, I.

Publications and source records attributed to Achilonu, I..

4 recordsLinked to original sources

bioRxiv2025

ClpK as a Chaperone Hub: Computational Exploration of its Protein Interaction Landscape.

Protein-protein interaction networks provide a foundation for understanding the molecular mechanisms within cells and are increasingly recognized as promising targets for therapeutic intervention. However, the experimental elucidation of these interactions is complicated by the complexity and dynamic nature of protein interaction networks. In silico methods have become invaluable allowing researchers to identify potential interactions and focus on those that may be biologically significant to guide experimental validation and drug discovery. This study employed computational modelling, visualization, and network analysis to investigate the interactions of ClpK, a Clp ATPase integral to protein homeostasis and thermotolerance of Klebsiella pneumoniae. Potential interacting partners of ClpK were predicted using the STRING database with ClpB used as a structural proxy for ClpK. The proteins with edge confidence scores greater than 0.8 were selected for molecular docking and molecular dynamics simulations to assess interaction stability and binding affinities. Molecular docking using the ClusPro server confirmed stable interactions between ClpK and its predicted partners, which were further characterised using PDBsum and Hawkdock to visualise binding interfaces and estimate binding free energies MM-GBSA calculation. Among the predicted complexes, KPN_01323 had the highest interaction score, highlighting it as the most promising candidate for further investigation. Molecular dynamics simulations further confirmed the stabilisation of putative partners upon interaction with ClpK supporting the robustness of this interaction. Collectively, these findings provide insight into the ClpK interaction network and establish a framework for future in vitro and in vivo studies contributing to elucidate the biological role and therapeutic potential of ClpK.

biochemistry↗

bioRxiv2023

Computational Identification of Potential Inhibitors Targeting cdk1 in Colorectal Cancer

Despite improved treatment options, colorectal cancer (CRC) remains a huge public health concern with a significant impact on affected individuals. Cell cycle dysregulation and overexpression of certain regulators and checkpoint activators are important recurring events in the progression of cancer. Cyclin-dependent kinase 1 (CDK1), a key regulator of the cell cycle component central to the uncontrolled proliferation of malignant cells, has been reportedly implicated in CRC. This study aimed to identify CDK1 inhibitors with potential for clinical drug research in CRC. Ten thousand (10,000) naturally occurring compounds were evaluated for their inhibitory efficacies against CDK1 through molecular docking studies. The stability of the lead compounds in complex with CDK1 was evaluated using molecular dynamics simulation for one thousand (1,000) nanoseconds. The top-scoring candidates ADME characteristics and drug-likeness were profiled using SwissADME. Four hit compounds namely spiraeoside, robinetin, 6-hydroxyluteolin, and quercetagetin were identified from molecular docking analysis to possess the least binding scores. Molecular dynamics simulation revealed that robinetin and 6-hydroxyluteolin complexes were stable within the binding pocket of the CDK1 protein. The findings from this study provide insight into novel candidates with specific inhibitory CDK1 activities that can be further investigated through animal testing, clinical trials, and drug development research for CRC treatment.

bioinformatics↗

bioRxiv2021

SARS-CoV-2 spike protein unlikely to bind to integrins via the Arg-Gly-Asp (RGD) motif of the Receptor Binding Domain: evidence from structural analysis and microscale accelerated molecular dynamics

The Receptor Binding Domain (RBD) of SARS-CoV-2 virus harbors a sequence of Arg-Gly-Asp tripeptide named RGD motif, which has also been identified in extracellular matrix proteins that bind integrins as well as other disintegrins and viruses. Accordingly, integrins have been proposed as host receptors for SARS-CoV-2. The hypothesis was supported by sequence and structural analysis. However, given that the microenvironment of the RGD motif imposes structural hindrance to the protein-protein association, the validity of this hypothesis is still uncertain. Here, we used normal mode analysis, accelerated molecular dynamics microscale simulation, and protein-protein docking to investigate the putative role of RGD motif of SARS-CoV-2 RBD for interacting with integrins. We found, by molecular dynamics, that neither RGD motif nore its microenvironment show any significant conformational shift in the RBD structure. Highly populated clusters were used to run a protein-protein docking against three RGD-binding integrin types, showing no capability of the RBD domain to interact with the RGD binding site. Moreover, the free energy landscape revealed that the RGD conformation within RBD could not acquire an optimal geometry to allow the interaction with integrins. Our results highlighted different structural features of the RGD motif that may prevent its involvement in the interaction with integrins. We, therefore, suggest, in the case where integrins are confirmed to be the direct host receptors for SARS-CoV-2, a possible involvement of other residues to stabilize the interaction.

bioinformatics↗

bioRxiv2020

Comparative characterisation of Plasmodium falciparum Hsp70-1 relative to E. coli DnaK reveals functional specificity of the parasite chaperone

Hsp70 is one of the most prominent molecular chaperones. Although Hsp70s from various organisms are generally conserved, they exhibit specialised cellular functions. It remains to be fully understood how these highly conserved molecules exhibit specialised functional features. Plasmodium falciparum Hsp70-1 (PfHsp70-1) is a cytosol localised molecular chaperone that is implicated in the cyto-protection and pathogenicity of the malaria parasite. In the current study, we investigated the comparative structure-function features of PfHsp70-1 relative to its homologue, E. coli Hsp70 (DnaK) and a chimeric protein, KPf, that was constituted by the ATPase domain of DnaK and the substrate binding domain (SBD) of PfHsp70-1. Recombinant forms of all the three Hsp70s exhibited similar secondary and tertiary structural fold. We further established that compared to DnaK, both KPf and PfHsp70-1 were more stable to heat stress and exhibited higher basal ATPase activity. A recombinant P. falciparum Hsp40 (PfHsp40) stimulated the ATPase activities of all the three Hsp70s. In addition, both PfHsp70-1 and KPf exhibited preference for asparagine rich peptides as opposed to DnaK. Furthermore, all the three proteins exhibited self-association capabilities in vitro. Recombinant P. falciparum adenosylmethionine decarboxylase (PfAdoMetDC) co-expressed in E. coli with either KPf or PfHsp70-1 was produced as a fully folded product. On the other hand, co-expression of PfAdoMetDC with heterologous DnaK in E. coli did not promote folding of the former. These findings demonstrated that the SBD of PfHsp70-1 regulates several functional features of the protein and that this molecular chaperone is tailored to facilitate folding of plasmodial proteins.

biochemistry↗