Summary
SARS-CoV-2 has not yet developed a heavy coat of O-linked sugars (O-glycosylation) on its spike protein because it simply hasn’t needed to. So far, the virus can still escape immunity cheaply and quickly by making small changes to its receptor-binding domain or shifting existing sugar shields. Adding lots of new O-glycans would make the spike protein fold poorly, reduce its ability to grab human cells, and cost the virus fitness without giving any real benefit—under today’s immune pressure. Other viruses (HIV, influenza) only built extensive glycan shields after years of intense antibody attack forced them to, and only after helpful compensating mutations appeared elsewhere in the protein to keep it stable. For SARS-CoV-2, large-scale O-glycosylation remains entirely possible but energetically expensive and unnecessary—until population-wide immunity (especially from repeated vaccination) becomes so strong that simpler escape routes are exhausted. At that point, the survival advantage of hiding behind a thick sugar cloak will outweigh the structural costs, and the virus will evolve it.
Source: https://voiceforscienceandsolidarity.substack.com/p/why-large-scale-o-glycosylation-on
Why Large-Scale O-Glycosylation on the SARS-CoV-2 Spike Protein Is Unlikely Until It Becomes Necessary
More and more people are using AI (artificial intelligence, which are computer programs that can generate text or answers) to pretend they’re experts in topics they don’t really know. This makes sense because it’s easy, but it’s obvious right away—especially when they use fancy technical words they couldn’t have learned from their unrelated background or education.
For instance, one of my followers replied to a recent post on Substack (a platform for writing and sharing articles) with this question: “@GVDBossche, can you explain what evidence or structural preconditions you see that would make a rapid, large-scale O-glycosylation expansion on the spike energetically feasible, given the trimer’s steric constraints and the consistent failure of such mutants so far?”
My predictions about the virus are bold and seem unbelievable or even ridiculous to most people. So, this criticism—probably created by AI—inspired me to write this article. It helps separate simple ideas from more advanced scientific thinking.
The Main Idea: Why Large-Scale O-Glycosylation on the SARS-CoV-2 Spike Hasn’t Happened Yet
There’s a common mistake in talks about how SARS-CoV-2 (the virus that causes COVID-19, often shortened to SC-2) might evolve in the future. People assume that because we haven’t seen a big increase in O-glycans (sugar molecules attached to proteins through oxygen atoms; this process is called O-glycosylation) on the spike protein (the “S” protein, a key part on the virus’s surface that helps it enter human cells), it must be impossible due to structural (physical shape) or energetic (energy-related) reasons. But that’s not true. The virus just hasn’t faced enough pressure from the immune system (the body’s defense against infections) to make this change worthwhile yet.
Here are the key reasons, explained simply with definitions for technical terms:
- Structural Limits Aren’t Set in Stone—They Depend on the Situation! It’s correct that when scientists try to engineer (artificially create) spike proteins with lots of O-glycans, they often don’t fold properly (folding is how proteins get their 3D shape to work right) or lose their ability to bind strongly to ACE2 (a protein receptor on human cells that the virus uses like a key to unlock and enter cells; “affinity” means how tightly they stick together). But viruses evolve (change over time through mutations, which are random genetic tweaks) to solve these issues when the benefits outweigh the downsides. For example, viruses like HIV-1 (the virus causing AIDS), H3N2 influenza (a type of flu virus), and others only added more glycans (sugars) to create a “glycan shield” (a protective layer of sugars that hides the virus from the immune system) after facing strong pressure from antibodies (proteins made by the immune system to fight invaders, often abbreviated as “Ab”). Right now, SARS-CoV-2 can still dodge the immune system easily in cheaper ways, like tweaking its RBD (Receptor Binding Domain, the specific part of the spike that grabs ACE2), remodeling loops in the NTD (N-Terminal Domain, the front end of the spike protein), shifting N-glycans (sugars attached through nitrogen atoms instead of oxygen), recombining (mixing genetic material from different virus strains), or making small helpful changes in how the spike’s parts (S1 and S2) move and interact (this affects how the virus fuses with cells). As long as these simple tricks work, adding lots of O-glycans would cost the virus more in fitness (its overall ability to survive, replicate, and spread) without any gain—so those mutated versions don’t take over.
- Immune Pressure Can Beat Physical Space Limits. When neutralizing antibodies (a type of antibody that specifically blocks the virus from infecting cells) cover all the exposed parts of the spike protein, even glycans that slightly destabilize (make less stable) the protein can become helpful. They do this by masking epitopes (the specific spots on the virus that antibodies target and recognize). Viral fitness isn’t about being perfectly structured in a lab—it’s about surviving in a “hostile” host (the infected person’s body, where the immune system is attacking). If the pressure from anti-spike antibodies keeps growing and the RBD runs out of easy mutation options (mutational space means the possible changes it can make without breaking), the virus will prioritize escaping the immune system over keeping its ideal physical efficiency.
- Adding Glycans Needs Other Changes to Evolve Together—The Pandemic Isn’t Over, So It Takes Time. O-glycosylation doesn’t happen on its own. For other viruses, big additions of glycans only work when other helpful mutations co-evolve (evolve at the same time) in related parts of the protein. These could be in areas like the trimer interface (where three spike proteins join to form a stable group called a trimer), the RBD hinge (a flexible joint in the binding domain), the S1-S2 coupling region (where the two main parts of the spike connect), or hydrophobic cores (water-repelling inner parts that help keep the protein stable in its pre-fusion state, before it enters a cell). SARS-CoV-2 can access these kinds of changes, but they haven’t been selected (chosen by natural selection, where better-adapted viruses spread more) yet because the virus doesn’t need them. The evolutionary dynamics (how the virus changes over time in response to its environment) for major shifts in the glycosylation profile (the pattern of sugar attachments on the protein) take time to develop.
- There Hasn’t Been a Reason to Evolve This Way… Yet. So far, SARS-CoV-2 has kept enough replication capacity (ability to make copies of itself) through regular “drift” (slow, ongoing changes in its genetic code, like amino-acid substitutions, which are swaps of building blocks in proteins). Escaping immunity this way is cheaper, faster, and less disruptive than adding extra glycans to the spike. This will stay true until widespread immunity in highly COVID-19-vaccinated populations (groups of people who’ve gotten many COVID shots) squeezes the virus so much that it struggles to infect and spread. In other words, when the environment changes to where: antibody pressure blocks the virus’s ability to invade cells overwhelmingly, RBD mutations are all used up, and antiviral cytokines (small signaling proteins released by immune cells to fight viruses) from ongoing CD4+ T cell stimulation (CD4+ T cells are helper immune cells that coordinate the body’s response) shut down productive infection—then adding O-glycans makes sense evolutionarily, even if it hurts ACE2 binding or fusion kinetics (the speed and process of merging with host cells).
- Evolution Doesn’t Aim for Perfection—It Aims for Survival. The fact that we haven’t seen spike variants (different versions of the virus) with heavy glycans doesn’t mean they’re impossible. It just means they’re not needed yet. Once the immune environment becomes tough enough, the virus will try glycan-based escapes, with other mutations compensating (balancing out) the destabilizing effects on the protein’s fold (shape) and trimer’s steric constraints (physical space limits that might cause clashes). In simple terms: O-glycosylation isn’t held back by structural rules. It’s waiting for the growing immune pressure from highly vaccinated populations to force the virus to adapt in this way to keep spreading.
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