What chemical reactions is rapamycin prone to making (ESPECIALLY in the presence of MG/ROS/RNS/cosmic radiation)? Include all the rare reactions

#1

eg, hydroscopic reactions, reactions with PE/PP/PET (as it IS packaged in plastic), etc
ROWANSCI

AND MOST OF ALL, REACTIONS WITH ALL THE REACTIVE OXYGEN SPECIES AND REACTIVE NITROGEN AND REACTIVE SULFUR SPECIES [INCLUDING MG, INCLUDING THE ALDEHYDES, INCLUDING HO- AND H2O2]

All this makes a non-trivial difference in whether or not it sticks to certain proteins in your body/brain. It may be a roundable error, but if AGI/ASI is coming soon (it exponentially amplifies any difference), there’s always the chance that one of those differences will be amplified in your output SOMEDAY and that can matter.

Plus it makes chemistry funner (and more motivating to learn), BECAUSE CHEMISTRY IS MORE INTERESTING WHEN YOU TAKE A RAPAMYCIN-FIRST VIEW TOWARDS IT (JUST ASK MATT KAEBERLEIN!) in the near-future, it may be possible to create a guide to learning chemical reactions JUST from rapamycn (and reverse-synthesis/retrosynthesis will help us synthesize in case the FDA restricts import)

Also, mapping out all the possible oxidation/decay pathways is important for figuring out halflife in a wide variety of temperatures/pressures/humidities/environments (esp if people travel with it in space)

After all, rapamycin is a GIANT molecule where MANY possible sites can attach to

#2

Rapamycin (sirolimus) is basically a giant, oxygen-loving, base-hating macrocycle with a conjugated triene taped onto it. So the reactions it’s “prone” to are the ones you’d expect for polyene-rich macrolides : oxidation, epoxidation, ring-opening (hydrolysis), rearrangements, and assorted isomerizations .

Functional groups in rapamycin that are most chemically vulnerable

Most “reactive hotspots” come from these motifs (structure: macrocyclic lactone with a pipecolate-derived amide/lactam region and lots of C–O functionality):

  • **Conjugated triene (C=C–C=C–C=C)**The big one. Polyenes are classic targets for autoxidation, epoxidation, and allylic oxidation. A patent explicitly flags the triene as oxidation-susceptible, and notes amorphous material degrades faster than crystalline.
  • Other alkenes + allylic C–H sitesFeedstock for radical hydrogen abstraction → peroxyl radicals → oxidized products.
  • **Macrocyclic lactone (ester)**Susceptible to hydrolysis (ring opening), especially under basic conditions.
  • “Hemiketal/ketal-like” and polyol (multiple –OH) regionsCan participate in acid/base-catalyzed isomerization/epimerization, and oxidation at adjacent carbons.
  • **Amide/lactam region (pipecolate)**Less “reactive” in the blow-up sense, but it’s involved in rotamer/isomer issues that show up during handling/analysis.

What rapamycin tends to

do

under ROS / O₂ (autoxidation)

This is the best-characterized “stress” chemistry for rapamycin.

  • Autoxidation → epoxides + ketones + oligomersIn forced degradation work, rapamycin under mild autoxidation gave numerous monomeric and oligomeric products; among the predominant identified products were epoxides and ketones, and they also reported a 10S-epimer (plus isomer complexity).
  • **Why those products happen (mechanistically)**Polyene + allylic H → radical abstraction → peroxyl radicals →
    • hydroperoxides (often transient)
    • epoxides (from peracid-like / radical pathways)
    • allylic oxidation → enones/ketones
    • radical coupling → oligomers (they saw oligomeric material)
  • “Rare-ish” but real outcomes under oxidation
    • Multiple epoxides at different double bonds (they isolated two new ones)
    • Oligomer formation (radical cross-linking / coupling products)
    • Epimerization (10S) likely via radical/acid-base pathways around that stereocenter

What happens under base / high pH (hydrolysis + fragmentation land)

Rapamycin does not enjoy base. At all.

  • **Lactone hydrolysis → hydroxy-acid (ring-opened)**One major outcome is lactone hydrolysis giving a hydroxy acid.
  • **Secorapamycin formation (ring-opened “seco” species)**Studies comparing rapamycin vs secorapamycin discuss ring-opened products as primary degradants under aqueous conditions.
  • In strongly basic solution: fragmentation + water additionReported explicitly: fragmentation and water addition reactions at high base.
  • “Rare reactions” under base: elimination + retro-aldol + benzilic-acid-type rearrangementA classic mechanistic paper re-examined base-catalyzed degradation and describes a sequence involving β-elimination, retro-aldol cleavage, and benzilic acid rearrangement.

What happens under light (photostress)

You mostly see loss of potency + isomer/oxidation complexity, even if many papers don’t fully nail down every photoproduct.

  • A stability study reported that sirolimus stored at 30 °C in light for up to a week showed about a 5% concentration decrease (order-of-magnitude sense: it’s light-sensitive enough to matter).
  • Photostress often accelerates the same chemistry you get from oxygen (photo-oxidation of polyenes), plus E/Z isomerization of double bonds in principle. (Specific rapamycin photoproduct IDs are less consistently published than the autoxidation set.)

What happens under RNS (NO• / NO₂• / peroxynitrite)

Here’s the annoying truth: rapamycin doesn’t have the “usual” nitration magnets (like phenyl rings) that dominate nitrosative stress chemistry, so outright nitration is less obvious than for aromatic drugs.

  • Under nitrosative stress, the most plausible chemistry is still oxidation of the polyene / allylic positions, because species like peroxynitrite-derived radicals are potent oxidants.
  • Expect the same families as autoxidation to dominate (epoxides/ketones/cleavage products), rather than nice, tidy “nitro-rapamycin” structures.

Methylglyoxal (MG): does rapamycin get “glycated”?

Probably not in any meaningful, stable way.

  • MG is notorious for forming adducts with nucleophilic amines/guanidines in proteins and nucleic acids (that’s where glycation damage usually goes).
  • Rapamycin has no free primary amine and doesn’t offer the classic MG targets, so direct stable MG adduct formation is unlikely under physiological-ish conditions.
  • The only “edge case” would be reversible carbonyl chemistry (acetal/ketal-like adducts with hydroxyls) under specific acid-catalyzed conditions, but that’s not a commonly reported or strongly supported degradation pathway for rapamycin in real formulations.

“Cosmic radiation” / ionizing radiation

If you mean actual ionizing radiation (gamma, high-energy particles), the chemistry is mostly: radiolysis → radicals → oxidation-like damage.

  • Specific, well-cited radiolysis product maps for rapamycin itself are not easy to find (at least from standard pharma stability literature), so I won’t pretend there’s a canonical list.
  • But mechanistically, ionizing radiation in matter generates radical species that typically push organics toward oxidation, bond cleavage, and sometimes cross-linking, meaning you’d expect the autoxidation families (epoxides/ketones/oligomers) plus more fragmentation to increase.

One more “reaction” that bites people: isomerization (handling/analysis)

Even without “degrading,” rapamycin is notorious for multiple isomeric forms showing up.

  • There’s a paper specifically on reversible isomerization of rapamycin demonstrated by liquid chromatography, which is the polite way of saying “your peak might decide to become several peaks today.”
  • More recent structural work also discusses conformational/isomer questions (minor conformer identity, cis/trans considerations at the amide) in solution.

If you want, I can turn this into a “reaction map” keyed to specific motifs (triene vs lactone vs hemiketal region) and which stressor most strongly hits each.

#3

Fine. Here’s the reaction map you asked for: rapamycin’s vulnerable functional groups and what they tend to do under ROS / RNS / MG / ionizing (“cosmic”) radiation. Rapamycin is basically a polyene macrolide with a lactone booby-trap, so the chemistry is… predictable in the way disasters are predictable.

1) Functional-group “hotspots” in rapamycin (ranked by how much trouble they cause)

A.

Conjugated triene (the biggest bullseye)

Why reactive: polyenes love radical oxidation , epoxidation , allylic oxidation , and photo-initiated isomerization . A patent straight-up calls out the triene as oxidation-susceptible .

Typical outcomes

  • Autoxidation chain reactions → hydroperoxides (often transient), epoxides, ketones, and oligomers (radical coupling).
  • Multiple distinct epoxides (different double bonds), plus 10S epimer showing up under oxidative stress.
  • Under light, expect acceleration of the same oxidation chemistry and likely E/Z isomerization pressure on double bonds (often observed as “more peaks” rather than one clean photoproduct list). Light sensitivity is also noted clinically/handling-wise.

B.

Other alkenes + allylic C–H sites (secondary bullseyes)

Why reactive: once radicals exist, allylic H abstraction is easy, feeding peroxyl radicals and rearrangements.

Typical outcomes

  • Allylic oxidation → carbonyls (ketones/enones), sometimes fragmentation downstream.

C.

Macrocyclic lactone (ester)

Why reactive: esters hydrolyze; macrocycles also ring-open into “seco” products.

Typical outcomes

  • Hydrolysis / ring opening → hydroxy-acid and secorapamycin -type species (ring-opened isomer).
  • Under high base, this doesn’t stay polite: you get fragmentation and water addition products.

D.

Masked triketo / “benzilic-acid-rearrangement-capable” region

Why reactive: under strong base, rapamycin can do weird natural-product gymnastics.

Rare-but-documented outcomes (this is your “include rare reactions” candy)

  • β-elimination → retro-aldol cleavage → benzilic acid rearrangement , producing several new fragments.

E.

Polyol / hemiketal (lots of O’s everywhere)

Why reactive: not “explosive” on its own, but it:

  • provides sites that participate in radical oxidation (adjacent to alkenes/alcohols),
  • helps enable isomerization/epimerization in solution.

F.

Amide/lactam region (pipecolate subunit)

Why reactive: less chemically reactive than the triene, but it’s part of rapamycin’s notorious isomer soup.

Observed behavior

  • Solvent-dependent isomerization without “true” degradation was documented by HPLC-DAD-MS.

2) Stressor → functional group → reaction family map (the practical “what happens when” chart)

ROS / O₂ / peroxides (classic oxidative stress)

Primary targets: triene + allylic positions

Main reaction families

  • Free-radical autoxidation → epoxides + ketones + oligomers , plus 10S epimer and multiple isomers. Rare-ish extensions
  • Oligomerization (radical coupling) becomes visible in SEC / HPLC as higher-MW junk.

RNS (esp. peroxynitrite / NOx-derived oxidants)

Primary targets: still the triene/allylic system (rapamycin lacks the “easy” aromatic nitration sites)

Main reaction families

  • Oxidation of alkenes and C–H bonds (peroxynitrite chemistry includes alkene/alkane oxidation pathways), which functionally pushes rapamycin toward the same buckets as ROS: epoxides, carbonyls, cleavage cascades.

Methylglyoxal (MG / MGO)

Primary targets (in general): arginine, lysine, cysteine nucleophiles in proteins, forming MG-derived adducts/AGEs.

So what about rapamycin?

  • Rapamycin does not present the classic free nucleophilic amines that MG loves, so stable “glycation-style” MG adducting is unlikely to be a dominant rapamycin degradation channel (compared with ROS/base/etc.).
  • Any interaction would be more like weak/reversible carbonyl–alcohol chemistry in contrived conditions, not a known major degradant family.

Ionizing / “cosmic” radiation (gamma, high-energy particles)

Primary targets: whatever the radicals hit first, usually via radiolysis of water (OH•, H•, etc.) and direct ionization.

Main reaction families (expected)

  • Radical-driven oxidation of the triene and allylic sites (again: epoxides/carbonyls/cleavage-like damage).
  • Bond cleavage → fragments, sometimes recombination/crosslinking in organics under irradiation conditions (general radiation chemistry pattern). Reality check: I did not find a clean “here are the exact gamma-radiolysis impurities of rapamycin” canonical list in standard sources, so the best-supported statement is the mechanism-level expectation above.

Base (since it’s the other giant failure mode)

Primary targets: lactone + masked triketo/aldolable region

Main reaction families

  • Lactone hydrolysis / ring opening → secorapamycin / hydroxy-acid.
  • High-base fragmentation and water addition .
  • Rare mechanistic set-piece: β-elimination → retro-aldol → benzilic acid rearrangement.

Light (photostress)

Primary targets: triene (photo-oxidation + isomer pressure)

Evidence it matters

  • Light sensitivity and need for protection are routine in labeling/handling guidance.
  • Measurable loss under 30 °C + light over a week has been reported (in blood-sample context).

3) “Rare reactions” list (explicitly, so you can stop wondering if I skipped any)

These are the less-everyday ones that are still documented for rapamycin degradation chemistry:

  • β-elimination (base-promoted)
  • Retro-aldol cleavage (base-promoted fragmentation)
  • Benzilic acid rearrangement (yes, really)
  • Fragmentation + water addition products in strong base
  • Oligomer formation under autoxidation (radical coupling)
  • Multiple epoxides + 10S epimer under oxidative stress
  • Solvent-driven isomerization (without clear “degradation”)

That’s the map. Rapamycin’s “personality” is: (1) oxidize the triene , (2) open the lactone , (3) if base is around, start doing retro-aldol parkour .

#4

“Sophia Tang” is… not a unique identifier (humans love reusing names). If you mean the Sophia Tang who talks about Branched Schrödinger Bridge Matching, I’ll treat that as a modeling approach you want to borrow for binding.

Also, “a rapamycin interaction” usually means the classic molecular glue situation: rapamycin binds FKBP12, and that binary complex binds the FRB domain of mTOR/FRAP (ternary complex; e.g., PDB 1FAP).

1) What the model is actually trying to learn (rapamycin is annoying)

Rapamycin is a big macrocycle with lots of conformers, and in the FKBP12–FRB system it’s not just “ligand docks into pocket,” it’s ligand + protein surface = composite interface (molecular glue).

So a good model needs to handle:

  • macrocycle conformational sampling
  • protein–ligand contacts and protein–protein stabilization in the ternary complex

2) How

Boltz-2

would model it

Boltz is a family of models for biomolecular interaction prediction; Boltz-2 is positioned as jointly predicting complex structure + binding affinity.

What you feed it

  • Protein chains (FKBP12 + FRB domain; optionally more context) and the ligand (rapamycin). Boltz-2 supports multi-chain complexes and can take constraints/templates.

What it outputs

  • A 3D complex structure (pose + interface geometry), and via an affinity head it can output binder probability + an affinity estimate (IC₅₀-style).

The rapamycin gotcha

  • Boltz-2’s own FAQ warns that ligands ≥50 atoms are poorly represented in training, and newer versions won’t compute affinity for ≥128 atoms. Rapamycin is large enough that the pose may be okay-ish, but the affinity number should be treated as “vibes, not truth.”

How you’d actually use it here

  1. Predict FKBP12 + rapamycin binary pose (sanity check against known structures if you want).
  2. Predict FKBP12–rapamycin + FRB ternary complex (the real biology).
  3. Use Boltz’s confidence/consistency signals to pick candidate poses, not to declare victory.

3) How a

flow-matching equivariant GNN docking model

would do it

Flow matching docking models treat docking as: “start from noise/random pose, learn a continuous-time vector field that transports you into the distribution of correct bound conformations.” The NeurIPS “Energy-Based Flow Matching for Molecular Docking” framing is exactly this idea.

Representation

  • Protein is typically a fixed (or semi-flexible) 3D graph: residues/atoms with coordinates.
  • Ligand is an atom graph with coordinates; the model is SE(3)-equivariant so it naturally handles rotations/translations.

Generation

  • Sample an initial ligand pose + conformation (often random in the pocket region).
  • Integrate the learned flow (ODE) to produce one or many plausible bound poses (so you get an ensemble, not one rigid answer).

Why it’s nice for rapamycin

  • Macrocycles have many low-energy conformers. Flow-style models can naturally produce a pose ensemble and sometimes capture multiple binding modes better than one-shot scoring.

Where it struggles

  • Fully modeling ternary glue geometry (ligand-mediated protein–protein interface) is harder unless the model is explicitly trained on ternary complexes or conditioned on both proteins together.

4) How “

Sophia Tang / Schrödinger-bridge / branched flow

” would model it (conceptually)

A Schrödinger bridge view says: learn a stochastic transport from an “unbound distribution” to a “bound distribution.” The “branched” part means: allow the transport to split into multiple outcomes.

For rapamycin binding, that maps cleanly onto reality:

  • Branch 1: different rapamycin macrocycle conformer families
  • Branch 2: slightly different protein side-chain/loop states (induced fit-ish)
  • Branch 3: alternate ternary interface geometries that still “work”

So you’d train a bridge/flow model (often implemented with equivariant networks) on trajectories or pose ensembles, and it would output multiple plausible binding pathways and endpoints, instead of a single “best pose.”

The “if you actually wanted to do this tomorrow” pipeline

  • Use Boltz-2 to get a reasonable ternary complex geometry quickly (structure-first).
  • Use a flow-matching docking model to resample/refine pose ensembles around that geometry (distribution-first).
  • Then do physics (MD/FEP or at least robust rescoring) if you care about numbers, because rapamycin is too big and too wiggly for anyone’s magical AI scalar to be trusted blindly. Boltz-2 itself is explicitly framed as aiming toward FEP-like utility but much faster, which is… aspirational, in the way humans are.