Inhibitors block a protein's function. Degraders remove the protein. That difference bypasses the feedback activation which limits inhibitors, and it is less vulnerable to resistance driven by target overexpression — and because degraders act catalytically, activity does not require sustained high occupancy.
The trade-off is difficulty. An inhibitor needs to bind one site. A degrader must hold the target and an E3 ligase at the same time, and the resulting ternary complex has to adopt a geometry that actually permits ubiquitin transfer. Lumina Bio has concentrated on treating that geometry problem computationally.
PROTAC — current focus
Molecular glue — extension
Ternary complex predictionDeep-learning co-folding of the bound complex.
Stability under dynamicsExtended simulation of the predicted structure.
Benchmarked against published structuresMeasured against active-state complexes in the literature.
Exhaustive lysine scanUbiquitination sites mapped, not assumed.
Independent cross-checkConfirmed by a method built on other principles.
An honest boundary
We report these as geometric feasibility assessments, not verification. Computation evaluates whether a productive arrangement is possible; actual degradation efficiency is established experimentally, and we do not describe one as the other.
Membrane context
A degrader can look perfect in solution and be impossible on the membrane.
We find that out before you commit to synthesis. Most degrader work models the ternary complex in water, but many of the proteins that matter never see that state — they sit on a membrane in a defined orientation, and that orientation decides where an E3 ligase can and cannot reach. We build those systems, run them, and hand back a result you can check.
Deliverable 01
Ternary dynamics in a bilayer
The whole system — target, degrader, E3 ligase and its adaptors — in an explicit lipid bilayer of the composition the biology calls for. We report whether the interactions that define the complex survive the run, residue by residue, with occupancy measured across the trajectory rather than read off one frame.
These systems are not small. A bilayer wide enough that the complex never meets its own periodic image, with explicit solvent and counter-ions throughout, runs to roughly six hundred thousand atoms.
Deliverable 02
Can the geometry be reached at all
An E3 ligase arriving at an anchored target has to fit somewhere, and part of the space around that target is taken up by the membrane itself. We measure how much of a trajectory admits a given ternary geometry and report it as a cost in kcal/mol, so it can be weighed against the other terms in your model.
This is the part solution-phase prediction cannot see.
Deliverable 03
System build, with the checks shown
If you run your own simulations, we will build and verify the system. Setup errors in this work are usually silent: the run completes, the numbers look reasonable, and the answer is wrong. Our protocol is twenty-two checks covering atom and charge bookkeeping, degrees of freedom, bilayer integrity, protein placement and orientation, and the chemistry of the bound ligand — which routinely passes every count-based check while being structurally incorrect.
The report is the deliverable, not an appendix to it.
Two orientations, not the convenient one
A membrane-anchored target does not hold a single pose. It samples several, and the pose you choose decides the answer you get. Building only the orientation that favours a complex is answering a question you have already decided.
So we build both of the states our sampling identifies, and we build them the same way: same composition, same construction procedure, same simulation engine, same equilibration protocol. Where the comparison is the deliverable, any difference in how the two sides were made is a difference you cannot subtract out afterwards.
If the two orientations agree, orientation is not the gate we suspected, and that is a result. If they diverge, it is a term solution-phase prediction cannot see at all.
One check worth naming
Our build protocol runs a fixed set of checks before anything is committed to production. Most are bookkeeping. One is worth naming because of how quietly it fails.
A periodic simulation repeats its box in every direction. If the box is not wide enough, a molecule interacts with its own image, and the run does not announce this. It completes. The energies look ordinary. The trajectory looks like a trajectory. The numbers are artefacts of a molecule feeling itself.
We measure that clearance explicitly, and we measure it on the fully assembled system rather than on the empty bilayer, because a bilayer with ample margin can lose all of it the moment a ternary complex is placed on it. Where the margin is short, the system is rebuilt wider before anything is run. This is cheaper than discovering it downstream, and far cheaper than not discovering it.
Checked against experiment — not against ourselves.
A method validated on its own results proves nothing. Ours is measured against published crystal structures and published experimental values, so anyone can pull the same references and check the arithmetic.
Independent benchmark
Does this just repeat what SPR already tells you?
It does not, and we checked. Taking three ternary complex structures published by an outside group, we computed our membrane compatibility metric for compounds whose cooperativity that same group had measured by SPR. Two of them differ 34-fold in cooperativity — α = 143 against α = 4.2 — and our metric could not tell them apart. The gap between the two values falls well inside the measurement uncertainty we later quantified, ±6.6 percentage points.
So the quantity we measure is not one the binding experiment already reports. It is orthogonal information, not a slower route to a number you can get from SPR.
It is also not a potency predictor — in that series, cooperativity dominated the outcome. Our contribution sits upstream of it: ruling out the geometries a membrane will not permit, before anyone commits to synthesis.
A published ternary complex, reproducedFrom crystallographic coordinates, 100 ns of unrestrained dynamics kept every interaction the structure paper identifies. The defining salt bridge held in every frame, at a mean distance matching the crystallographic value.
Ligand parameters with no hand correctionAcross 298–1,486 Da, including degraders with more than twenty rotatable bonds. No missing parameters, no substituted analogies.
Bilayer properties against measurementThickness within 0.2% of the scattering value, and the order parameter profile reproduced along both acyl chains — including the dip at the site of unsaturation.
Orientation behaviour against the literatureReproduced, including its dependence on lipid composition. Published studies reached those states with microseconds of sampling; ours arrived within hundreds of nanoseconds, confirmed across independent repeats.
Two orientations carried in parallelBoth membrane states are constructed from the same procedure and equilibrated under the same protocol, so the comparison between them rests on the orientation and not on how each was assembled.
What survives more samplingExtending our trajectories by a factor of three cut the absolute compatibility values by more than half. The ordering of compounds did not change, and neither did which pairs the method cannot separate. We report rankings and separability rather than absolute values, because those are what held.
Experimental follow-up
Where a project needs wet-lab confirmation, we arrange it through contract laboratories — yours if you have one you trust, ours if you do not — and fold the results back into the model.
What we measure is geometric feasibility, not degradation efficiency: the two are established by different means and we do not describe one as the other. The full verification checklist, and a plain statement of what this method can and cannot settle, are available on request or at a scoping call.