Biology subjects

Aliper, E. T.

Publications and source records attributed to Aliper, E. T..

3 recordsLinked to original sources

bioRxiv2025

Immune Antibodies Recognizing the Stem Region of SARS-CoV-2 Spike Protein: Molecular Modelling and In Vitro Study of Synthetic Peptides Presentation to the Antibodies

Antibodies to peptide 1147 (amino acids 1147-61) of the SARS-CoV-2 protein S are highly diagnostic. Peptide 1147, although located in a region that is partly spatially hidden in the intact protein, is not subject to mutations, suggesting therapeutic potential. The aim of this study was to elucidate the architecture of this region and the way in which it is presented to antibodies. As a model system, this peptide carrying a single lipophilic tail and the same peptide carrying a lipophilic tail at both ends (pseudocyclic) were incorporated into lipid membrane. Isolated anti-1147 antibodies interacted with it regardless of how the peptide was presented, be that freely exposed via the N-terminus, organized as a pseudocycle, or adsorbed on the surface. MDS showed that peptide 1147 is capable of closely approaching the membrane. Analysis of the surface properties of peptide 1147 in membrane-bound states and in available conformations in the full-sized S protein reveals interface for interaction with antibodies. Interestingly, the latter bears similarities to one published peptide-antibody complex. However, these antibodies, in spite of their high diagnostic significance, show no virus-neutralizing activity, indicating that peptide 1147 has no therapeutic value as a synthetic vaccine.

immunology↗

bioRxiv2024

Lipid specificity of action of SARS-CoV-2 fusion peptide fragments on model membranes

The study focuses on investigating the interaction of SARS-CoV-2 fusion peptide fragment with model membranes of various lipid composition to elucidate the molecular mechanisms of peptide-derived membrane fusion. The work utilized the short fragment of SARS-CoV-2 fusion peptide which is homologous to 816-827 region of the native SARS-CoV-2 FP (FP816-827) and contains the highly conserved LLF motif responsible for membrane fusion, and its ineffective analogue (mFP816-827), where LLF motif was replaced for AAA. Using fluorescence fusion assay, it was demonstrated that the LLF motif plays a key role in inducing liposome fusion, whereas its replacement completely abolishes this capability. The fusogenic activity of the peptide strictly depended on the vesicle lipid composition. It was potentiated by phosphatidylethanolamine and inhibited by phosphatidylserine. Molecular dynamics revealed that both peptides predominantly adopt an -helical conformation; however, the native peptide interacts more strongly with the hydrophobic core of the membrane by increasing peptide-lipid hydrophobic contacts, while the mutant version exhibits a more superficial localization. Differential scanning microcalorimetry data indicated that the ability of FP816- 827 to disturb lipid packing increased with decreasing membrane lipid tail length. The molecular mechanisms underlying the fusogenic activity of the SARS-CoV-2 fusion peptide were identified, specifically its ability to cluster phospholipid head groups in its own vicinity. As a result, local regions with positive spontaneous curvature are formed in the outer monolayer, facilitating membrane fusion. The findings highlight the role of membrane composition and lipid architecture in the mechanism of viral fusion with host cells.

biophysics↗

bioRxiv2022

A uniquely stable trimeric model of SARS-CoV-2 spike transmembrane domain

The spike (S) protein of SARS-CoV-2 effectuates membrane fusion and virus entry into target cells. Its transmembrane domain (TMD) represents a homotrimer of -helices anchoring the spike in the viral envelope. Although S-protein models available to date include the TMD, its precise configuration was given brief consideration. Understanding viral fusion entails realistic 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 (S-TMD) based solely on its primary structure. First, we performed amino acid sequence pattern matching and compared molecular hydrophobicity potential (MHP) distribution on the helix surface against TM homotrimers with known 3D structures and thus selected the TMD of the tumour necrosis factor receptor 1 (TNFR-1) for subsequent template-based modelling. We then iteratively built an all-atom homotrimer model of S-TMD based on "dynamic MHP portraits" and residue variability motifs. In this model each helix possessed two overlapping interfaces interacting with either of the remaining helices, which include conservative residues I1216, F1220, I1227, M1229, and M1233. Finally, the stability of this and several alternative models (including a recent NMR structure) and a set of mutant forms was tested in all-atom molecular dynamics (MD) simulations in a POPC bilayer mimicking the viral envelope membrane. Unlike other configurations, our model trimer remained extraordinarily tightly packed over a microsecond-range MD and retained its stability when palmitoylated in accordance with experimental data. Palmitoylation had no significant impact on the TMD conformation nor the way in which the lipid bilayer was perturbed in the presence of the trimer. Overall, the resulting model of S-TMD conforms to known basic principles of TM helix packing and will be further used to explore the complex machinery of membrane fusion from a broader perspective beyond the TMD.

bioinformatics↗