A Uniquely Stable Trimeric Model of SARS-CoV-2 Spike Transmembrane Domain

Abstract

Understanding fusion mechanisms employed by SARS-CoV-2 spike protein entails realistic transmembrane domain (TMD) models, while no reliable approaches towards predicting the 3D structure of transmembrane (TM) trimers exist. Here, we propose a comprehensive computational framework to model the spike TMD only based on its primary structure. We performed amino acid sequence pattern matching and compared the molecular hydrophobicity potential (MHP) distribution on the helix surface against TM homotrimers with known 3D structures and selected an appropriate template for homology modeling. We then iteratively built a model of spike TMD, adjusting “dynamic MHP portraits” and residue variability motifs. The stability of this model, with and without palmitoyl modifications downstream of the TMD, and several alternative configurations (including a recent NMR structure), was tested in all-atom molecular dynamics simulations in a POPC bilayer mimicking the viral envelope. Our model demonstrated unique stability under the conditions applied and conforms to known basic principles of TM helix packing. The original computational framework looks promising and could potentially be employed in the construction of 3D models of TM trimers for a wide range of membrane proteins.

Prospecting native and analogous peptides with anti-SARS-CoV-2 potential derived from the trypsin inhibitor purified from tamarind seeds

“…It is relevant to highlight the mixture of POPC and POPS used to build the TMPRSS2 model served to ensure structural stability during MD simulations ( Aliper et al, 2022 ) due to the presence of hydrophobic tails in these phospholipids ( Kumar and Sastry, 2021 ). Therefore, suggesting that hydrophobic interactions mediate structural stability.…”

Inconspicuous Yet Indispensable: The Coronavirus Spike Transmembrane Domain

“…In this structure, the TM helix started at Y1215 and ended at L1234; however, W1212 was also entirely buried in the lipid bilayer, suggesting certain structural continuity across residues 1212 to 1234 (cf. predictions in [20]). In any event, seeing precise boundaries between domains might be fuzzy and might vary between different conformational states.…”

“…Different SARS-CoV-2 spike TMD boundaries were predicted with recourse to TM-SEG [15] (TMD residues: 1214-1238) and TMPRED [16] (1216-1235) or proposed on the basis of data from UniProt [17] entry P0DTC2 (1214-1234), as well as in the work by Xia et al [18] (1213-1237) and Cai et al [19] (1212-1234). Finally, region 1212-1234 was predicted by Aliper et al [20] based on the results of an MC conformational search in the presence of an implicit membrane known as a "hydrophobic slab". In this case, the TMD is flanked by Lys1211 and Cys1235, the first Cys residue among the many to follow downstream.…”

“…In a solution NMR study of a SARS-CoV-2 spike monomeric fragment spanning lower HR2 to the N-terminal Cys-rich region [22], it was observed that the side chains of W1214 and W1217 are buried in the lipid medium, whilst W1212 tends to be exposed to the solvent. The behaviour of the aromatic cluster as part of the TMD region 1212-1234 was also evaluated in silico using MC simulations with a hydrophobic slab [20]. It was shown that in the most energetically favourable MC-states the entire TM peptide is embedded into the hydrophobic medium and does not expose the N-terminal fragment W1212-W1217 at the lipid/water interface.…”

Progress of the “Molecular Informatics” Section in 2022

“…In 2022, the number of closed SIs was 22, and the top SI based on the number of published articles and visualizations was the one dedicated to "Deep Learning and Machine Learning in Bioinformatics" . We also saw many publications on COVID-19 and SARS-CoV-2, with 49 papers published on this topic between 2020 and 2023 [2,10,12,.…”