Maryam Ghasemitarei

Reactive oxygen species generated during inflammation can oxidize viral envelope lipids, with outcomes ranging from modulated infectivity to viral inactivation.

Reactive oxygen species generated during inflammation can oxidize viral envelope lipids, with outcomes ranging from modulated infectivity to viral inactivation. For SARS-CoV-2, the molecular mechanisms by which membrane lipid oxidation influences spike protein anchoring remain poorly understood. We use all-atom molecular dynamics (MD) simulations to quantify how graded oxidation of 1-palmitoyl-2-oleoyl- sn -glycero-3-phosphocholine (POPC) affects the anchoring of the SARS-CoV-2 spike transmembrane (TM) region in an endoplasmic-reticulum–Golgi intermediate compartment (ERGIC)-like multicomponent membrane. Viral envelopes containing 0, 25, 50, 75, and 100% oxidized POPC (PoxnoPC) corresponding to 0 − 55% oxidation of all PO-type phospholipids were simulated with the spike TM helix and cytoplasmic tail embedded in a POPC/POPE/POPI/POPS/cholesterol mixture. Steered MD and umbrella sampling were used to calculate the potential of mean force (PMF) for extracting the TM+CT region along the membrane normal. Partial oxidation (25 − 75% POPC) produced reductions in the detachment barrier that were not statistically distinguishable from the native system within the sampling uncertainty, whereas full POPC oxidation lowered the anchoring free energy by about 23% (from 606 ± 39 to 464 ± 38 kJ mol ⁻¹ ), indicating that oxidation of roughly half of the glycerophospholipids can measurably weaken spike-membrane coupling. Despite this reduction, the remaining barrier (about 180 k _B T ) is still large, suggesting that oxidation alone may be insufficient for spontaneous spike detachment and likely acts synergistically with mechanical forces during fusion or immune engagement. Analysis of acyl-chain order parameters, area per lipid, membrane thickness, number-density profiles, and lateral lipid clustering reveals that POPC peroxidation decreases lipid order, thins and softens the bilayer, and disrupts cholesterol-stabilized clusters that refer to large cooperative lipid assemblies (>10 lipids) identified via RDF-based clustering. These oxidation-induced changes reduce hydrophobic matching around the TM helix and facilitate its extraction from the viral envelope. Our results provide a mechanistic link between lipid peroxidation, membrane nanostructure, and spike anchoring, supporting lipid oxidation for example during cold atmospheric plasma or ozone treatment as a physically grounded contributing antiviral mechanism against SARS-CoV-2.

This study investigates the effect of cysteine (Cys) oxidation on the conformational changes of the SARS-CoV-2 Spike (S) protein, a critical factor in viral attachment and entry into host cells. Using targeted molecular dynamics (TMD) simulations, we explore the conformational transitions between the down (inaccessible) and up (accessible) states of the SARS-CoV-2 S protein in both its native and oxidized forms. Our findings reveal that oxidation significantly increases the energy barrier for these transitions, as indicated by the work required to move from the down to the up conformation and vice versa. Specifically, in the oxidized system compared to the native system, the energy required to transition from the down to the up conformation increases by approximately 131 ± 1 kJ.mol -1 , while the energy required for the reverse transition increases by about 223 ± 6 kJ.mol -1 . This is due to the stabilizing effect of oxidation on the conformation of the SARS-CoV-2 S protein. Analysis of hydrogen bond and salt bridge formation before and after oxidation provides additional insights into the stabilization mechanisms, showing an increase in salt bridge formation that contributes to conformational stabilization. These results underscore the potential of targeting translational modifications to hamper viral entry or enhance susceptibility to neutralization, offering a novel perspective for antiviral strategy development against SARS-CoV-2. This study adds important knowledge to the field of viral protein dynamics and highlights the critical role of structural and computational biology in uncovering new therapeutic avenues.

Plasma medicine, or the biomedical application of cold atmospheric plasma (CAP), is an expanding field within plasma research. CAP has demonstrated remarkable versatility in diverse biological applications, including cancer treatment, wound healing, microorganism inactivation, and skin disease therapy. However, the precise mechanisms underlying the effects of CAP remain incompletely understood. The therapeutic effects of CAP are largely attributed to the generation of reactive oxygen and nitrogen species (RONS), which play a crucial role in the biological responses induced by CAP. Specifically, RONS produced during CAP treatment have the ability to chemically modify cell membranes and membrane proteins, causing nitro-oxidative stress, thereby leading to changes in membrane permeability and disruption of cellular processes. To gain atomic-level insights into these interactions, non-reactive molecular dynamics (MD) simulations have emerged as a valuable tool. These simulations facilitate the examination of larger-scale system dynamics, including protein-protein and protein-membrane interactions. In this comprehensive review, we focus on the applications of non-reactive MD simulations in studying the effects of CAP on cellular components and interactions at the atomic level, providing a detailed overview of the potential of CAP in medicine. We also review the results of other MD studies that are not related to plasma medicine but explore the effects of nitro-oxidative stress on cellular components and are therefore important for a broader understanding of the underlying processes.

Binding of the SARS-CoV-2 S-glycoprotein to cell receptors is vital for the entry of the virus into cells and subsequent infection. ACE2 is the main cell receptor for SARS-CoV-2, which can attach to the C-terminal receptor-binding domain (RBD) of the SARS-CoV-2 S-glycoprotein. The GRP78 receptor plays an anchoring role, which attaches to the RBD and increases the chance of other RBDs binding to ACE2. Although high levels of reactive oxygen and nitrogen species (RONS) are produced during viral infections, it is not clear how they affect the RBD structure and its binding to ACE2 and GRP78. In this research, we apply molecular dynamics simulations to study the effect of oxidation of the highly reactive cysteine (Cys) amino acids of the RBD on its binding to ACE2 and GRP78. The interaction energy of both ACE2 and GRP78 with the whole RBD, as well as with the RBD main regions, is compared in both the native and oxidized RBDs. Our results show that the interaction energy between the oxidized RBD and ACE2 is strengthened by 155 kJ/mol, increasing the binding of the RBD to ACE2 after oxidation. In addition, the interaction energy between the RBD and GRP78 is slightly increased by 8 kJ/mol after oxidation, but this difference is not significant. Overall, these findings highlight the role of RONS in the binding of the SARS-CoV-2 S-glycoprotein to host cell receptors and suggest an alternative mechanism by which RONS could modulate the entrance of viral particles into the cells.