tetano
Editor, Senior Moderator
Int J Biol Macromol
. 2023 Nov 7:127986.
doi: 10.1016/j.ijbiomac.2023.127986. Online ahead of print. Lipid and cholesterols modulate the dynamics of SARS-CoV-2 viral ion channel ORF3a and its pathogenic variants
Madhusmita Rout[SUP] 1 [/SUP], Sarbani Mishra[SUP] 1 [/SUP], Sunita Panda[SUP] 2 [/SUP], Budheswar Dehury[SUP] 3 [/SUP], Sanghamitra Pati[SUP] 4 [/SUP]
Affiliations
SARS-CoV-2 accessory protein, ORF3a is a putative ion channel which immensely contributes to viral pathogenicity by modulating host immune responses and virus-host interactions. Relatively high expression of ORF3a in diseased individuals and implication with inflammasome activation, apoptosis and autophagy inhibition, ratifies as an effective target for developing vaccines and therapeutics. Herein, we present the elusive dynamics of ORF3a-dimeric state using all-atoms molecular dynamics (MD) simulations at μ-seconds scale in heterogeneous lipid-mimetic system in multiple replicates. Additionally, we also explore the effect of non-synonymous pathogenic mutations on ORF3a ion channel activity and viral pathogenicity in different SARS-CoV-2 variants using various structure-based protein stability (ΔΔG) tools and computational saturation mutagenesis. Our study ascertains the role of phosphatidylcholines and cholesterol in modulating the structure of ORF3a, which perturbs the size and flexibility of the polar cavity that allows permeation of large cations. Discrete trend in ion channel pore radius and area per lipid arises the premise that presence of lipids might also affect the overall conformation of ORF3a. MD structural-ensembles in some replicates rationalize the crucial role of TM2 in maintaining the native structure of ORF3a. We also infer that loss of stability primarily grounds for pathogenicity in more than half of the pathogenic variants of ORF3a. Overall, the effect of mutation on alteration of ion permeability of ORF3a, proposed in this study brings mechanistic insights into variant consequences on viral membrane proteins of SARS-CoV-2, which can be utilized for the development of novel therapeutics to treat COVID-19 and other coronavirus diseases.
Keywords: Membrane proteins; Molecular dynamics; Mutations; ORF3a; Protein stability; SARS-CoV-2.
. 2023 Nov 7:127986.
doi: 10.1016/j.ijbiomac.2023.127986. Online ahead of print. Lipid and cholesterols modulate the dynamics of SARS-CoV-2 viral ion channel ORF3a and its pathogenic variants
Madhusmita Rout[SUP] 1 [/SUP], Sarbani Mishra[SUP] 1 [/SUP], Sunita Panda[SUP] 2 [/SUP], Budheswar Dehury[SUP] 3 [/SUP], Sanghamitra Pati[SUP] 4 [/SUP]
Affiliations
- PMID: 37944718
- DOI: 10.1016/j.ijbiomac.2023.127986
SARS-CoV-2 accessory protein, ORF3a is a putative ion channel which immensely contributes to viral pathogenicity by modulating host immune responses and virus-host interactions. Relatively high expression of ORF3a in diseased individuals and implication with inflammasome activation, apoptosis and autophagy inhibition, ratifies as an effective target for developing vaccines and therapeutics. Herein, we present the elusive dynamics of ORF3a-dimeric state using all-atoms molecular dynamics (MD) simulations at μ-seconds scale in heterogeneous lipid-mimetic system in multiple replicates. Additionally, we also explore the effect of non-synonymous pathogenic mutations on ORF3a ion channel activity and viral pathogenicity in different SARS-CoV-2 variants using various structure-based protein stability (ΔΔG) tools and computational saturation mutagenesis. Our study ascertains the role of phosphatidylcholines and cholesterol in modulating the structure of ORF3a, which perturbs the size and flexibility of the polar cavity that allows permeation of large cations. Discrete trend in ion channel pore radius and area per lipid arises the premise that presence of lipids might also affect the overall conformation of ORF3a. MD structural-ensembles in some replicates rationalize the crucial role of TM2 in maintaining the native structure of ORF3a. We also infer that loss of stability primarily grounds for pathogenicity in more than half of the pathogenic variants of ORF3a. Overall, the effect of mutation on alteration of ion permeability of ORF3a, proposed in this study brings mechanistic insights into variant consequences on viral membrane proteins of SARS-CoV-2, which can be utilized for the development of novel therapeutics to treat COVID-19 and other coronavirus diseases.
Keywords: Membrane proteins; Molecular dynamics; Mutations; ORF3a; Protein stability; SARS-CoV-2.