LabBench
Assess a hidden binding pocket at the NRF2–BTRCP interface
This evaluation grades a saved answer independently. The original solver trajectory and prompt are preserved separately from the regrade; this is not a new solver attempt.
Read the task instructions and deliverables
# Assess a hidden binding pocket at the NRF2–BTRCP interface The team is studying whether small molecules can stabilize the contact between NRF2 and BTRCP, a protein that helps mark proteins for removal. Review the supplied slide excerpts and choose one structural model to guide interpretation of the Nurix compound at the SDS1–BTRCP interface. State one preferred model first; if you discuss alternatives, explain why they are weaker. A tied or unranked list is not a decision. Write model-review.md. Explain your choice using the reference structures, pocket comparisons, pose-stability plots, and structural overlays. Separate what the records establish from claims that still need measurement. Cite the relevant pages and plotted samples. Treat this as a retrospective review of completed modeling, not a request to reconstruct a calendar sequence or propose a new experiment plan.
How was it graded?
Agent-judged binary criteria.
Fraction of criteria passed; every criterion has weight one.
LLM judge: gpt-6.1-sol
Task files
Choose an evidence file.
Grading criteria
Interpret the pocket map as a result across simulated motion
Earns credit
interprets the 500 ns/1000-frame map as recurring pocket geometry and calculates that a displayed point occurred in at least 501 sampled frames because the threshold is strictly greater than 50%. Explains that these are frames containing a pocket point, not frames containing a bound ligand.
Does not earn credit
merely says persistent pocket or not binding probability without applying the strict threshold to 1000 frames, gives 500 as the minimum, or treats the count as ligand occupancy.
Accepted alternatives
More than 500 of the 1000 frames is equivalent to at least 501; no claim of statistically independent frames is required.
Weight: 1
Input evidence
Reference evidence
S079 · Slide 96, pocket-finding method
The scientist defines a motion-based pocket map, rather than a single structural snapshot.
Recorded result / GPT 6.1 sol
The review correctly describes recurring pocket geometry rather than ligand occupancy. However, it repeats the >50% threshold without calculating that a displayed point must occur in more than 500, or at least 501, of the 1,000 frames.
Keep the reference phosphorylation comparison matched
Earns credit
identifies first-pSer 6M93 and 1P22 after removal of its second phosphate. Compares their displayed interface-pocket extent in both the top and side views on page 8, and explains why the same phosphate count does not make the displayed template geometries equivalent.
Does not earn credit
only gives reference identifiers or phosphate labels, assumes unchanged double-pSer 1P22, reads just one view, or claims equivalent geometry without the plotted comparison.
Accepted alternatives
In the top view, 6M93 has broader regions extending on both sides of the central blue cavity, while modified 1P22 has more compact regions mainly to its left/upper side. In the side view, 6M93 has broad upper flanking regions as well as a downward extension; 1P22 has a smaller upper patch and narrower lower extension. Equivalent accurate visual comparisons are accepted; no volume is required.
Weight: 1
Input evidence
Reference evidence
S079 · Slide 99, reference-state labels and both pocket views; slide 100, reference recovery
The source compares first-pSer 6M93 with 1P22 after removing its second phosphate, while both displayed views retain distinct pocket extents.
Recorded result / GPT 6.1 sol
The review correctly identifies first-pSer 6M93 and phosphate-edited 1P22, and explains why their geometries need not match. Its broad yellow-versus-red comparison does not describe the pocket extent in both the top and side views, as required.
Use reference pose recovery as the method check
Earns credit
uses the labeled docked/X-ray Nurix overlay at the beta-catenin interface to describe at least two corresponding ligand features that overlap in a page-9 view. Explains why corresponding position and orientation support recovery of a known pose, rather than merely finding the same cavity.
Does not earn credit
only says colored sticks occupy the same region, cites pocket size alone, gives fewer than two corresponding ligand features, substitutes ARP4, or invents an RMSD.
Accepted alternatives
Two aligned ring systems, or a ring system and the connecting chain/second ring segment, are acceptable when their positions in the same view are described clearly. Exact chemical names and numerical deviations are not required.
Weight: 1
Input evidence
Reference evidence
S079 · Slide 100, second–fourth bullets and two ligand overlays; reference/human-record.pdf page 1
The scientist judges that docking recovers the X-ray pose and supports pocket finding in this example.
Recorded result / GPT 6.1 sol
The review describes general visual agreement in the beta-catenin overlay, but does not identify two corresponding ligand features. Sharing an interface region alone does not demonstrate recovery of the ligand's position and orientation.
Bound the reference validation
Earns credit
connects the successful beta-catenin docked/X-ray comparison on pages 8–9 with the internal SDS1 structure on page 15 that still lacks the Nurix pocket. Explains that reference pose recovery supports the method in that example but cannot settle accommodation in the different SDS1 interface.
Does not earn credit
only gives a generic does-not-validate-NRF2 disclaimer without the reference-success versus SDS1-pocket-absence comparison, or treats reference success as proof of SDS1 binding.
Accepted alternatives
Case-specific positive control is equivalent wording, provided both source comparisons and the transfer limit are expressed.
Weight: 1
Input evidence
Reference evidence
S079 · Slide 100, final bullet
The scientist explicitly limits agreement with experiment to this example.
S079 · Slide 106, first bullet; reference/human-record.pdf page 4
The scientist reports the SDS1 mismatch after the reference method check.
Recorded result / GPT 6.1 sol
The review limits successful beta-catenin pose recovery to that reference context, then contrasts it with the internal SDS1 structure that lacks the Nurix pocket. Its weaker ranking of direct template transfer makes clear why reference success cannot settle SDS1 accommodation.
Choose the better SDS1 pocket from retained poses
Earns credit
prefers SDS1 pocket 2 using two matched compounds across both page-11 pocket blocks. For each compound, identifies at least one retained pocket-2 pose by complex number and contrasts it with that compound’s three rejected pocket-1 poses. An unambiguous statement that every pocket-1 pose is rejected supplies the pocket-1 side of both matched comparisons when combined with the two named retained pocket-2 poses. Also names one compound with no retained pocket-2 pose.
Does not earn credit
states only a block-level preference without two correct named retained pocket-2 compound/complex pairs and their pocket-1 rejection comparison, omits a compound with no retained pocket-2 pose, uses SDS3 as SDS1, or claims every compound has a retained pocket-2 pose. Do not fail a complete universal-pocket-1 plus named-pocket-2 comparison solely because the universal rejection is not repeated for each compound.
Accepted alternatives
Choose any two: 0002 complex1/2; 0065 complex1/2; 0085 complex1/2/3; 0216 complex1/3; 0233 complex1; 0252 complex1. For each, pocket-1 complex1–3 are rejected. Either 0226 or 0253 has no retained pocket-2 pose. Prefix ARP4 and zero padding may be omitted if identity remains clear. Grouped and repeated matched comparisons are equivalent: for example, every pocket-1 pose is rejected; pocket 2 retains 0002 complex2 and 0065 complex2; 0226 has no retained pocket-2 pose. The universal statement must unambiguously cover all three pocket-1 poses for both named compounds; a vague preference or compound names without retained complex identifiers is insufficient.
Weight: 1
Input evidence
Reference evidence
S079 · Slide 102, both plot blocks and final two bullets; reference/human-record.pdf page 2
The scientist finds no stable pocket-1 pose but at least one stable pocket-2 pose in most cases.
Recorded result / GPT 6.1 sol
The review prefers pocket 2, explicitly states that all three poses of every compound are rejected in pocket 1, and names retained pocket-2 poses 0002 complex2 and 0065 complex2. It also correctly identifies 0226 and 0253 as having no retained pocket-2 poses. This meets the allowed grouped comparison.
Do not replace pose retention with a score alone
Earns credit
uses a specific crossed-out pocket-1 pose, such as ARP4-0065 complex2, to explain why a low CompScore alone cannot override the judgment that the pose leaves the pocket; the relevant evidence is stable retention under perturbation.
Does not earn credit
ranks poses solely by a score, ignores the rejection marks, or states lower is better without a specific score-versus-retention example.
Accepted alternatives
Another clearly low-score but rejected pocket-1 pose, compared with a retained pocket-2 pose, is acceptable.
Weight: 1
Input evidence
Reference evidence
S079 · Slides 84 and 102, stability explanation and pocket-1 rejection
The human stability judgment rejects poses that leave even when an isolated score appears attractive.
Recorded result / GPT 6.1 sol
The review explains retention under perturbation and specifically identifies pocket-1 ARP4-0065 complex2 as rejected despite its relatively low score. It correctly explains why a favorable score cannot override failure to remain in the pocket.
Separate SDS3 results from SDS1 results
Earns credit
compares all three ARP4-0253 poses in each of the two first-pSer SDS1 pockets with those in the no-pSer SDS3 pocket: all six SDS1 poses are rejected; SDS3 complex1 and complex2 are retained but complex3 is rejected. Explains that both peptide identity and phosphorylation condition change, so this comparison cannot identify either change alone as the cause.
Does not earn credit
only says 0253 is retained in SDS3, omits the three-block pose accounting, merges the models, or assigns the cause solely to phosphorylation or solely to peptide sequence.
Accepted alternatives
ARP4-253 and ARP4-0253 are equivalent identifiers. A compact table plus the explicit two-factor inference is acceptable.
Weight: 1
Input evidence
Reference evidence
S079 · Slides 102 and 104, condition labels and plot blocks
The 0253 panels reject complex1–3 in both SDS1 blocks, retain complex1/2 but reject complex3 in SDS3; both segment and phosphate condition differ.
Recorded result / GPT 6.1 sol
The review identifies the different SDS1 and SDS3 conditions and describes 0253 retention. However, it does not explain that peptide identity and phosphorylation change together, preventing either factor alone from being identified as the cause. It also leaves the SDS3 complex3 rejection unstated.
Commit to the opened SDS1 interface as the working structural model
Earns credit
states one preferred model first: the xenon-assisted opened SDS1–BTRCP interface as a provisional explanation for Nurix accommodation. Uses the reported static SDS1/HTRF mismatch, Leu motion away from the entry, and the displayed opened-interface ligand fit. Preserves the closed X-ray state as a valid starting observation, but explains why Leu motion and modeled ligand fit prevent using static pocket absence as an absolute binding veto. Does not claim measured SDS1 binding or proven molecular-glue action.
Does not earn credit
only selects the opened model and repeats the mismatch without reconciling closed and opened states; dismisses the X-ray structure as incorrect; treats static pocket absence as an absolute veto; selects SDS3; claims proven binding/glue action; or buries the opened state in a tie or unranked list.
Accepted alternatives
An ensemble with both closed and opened SDS1 states is acceptable only if the opened state is first for explaining accommodation and the closed-state observation is retained. A final explicit correction with the required evidence can recover the decision; an unresolved contradiction cannot.
Weight: 1
Input evidence
Reference evidence
S079 · Slide 106, fifth and sixth bullets; slide 107
The human concludes that the opened interface can house Nurix in the reference-like pose while the peptide interaction remains similar.
Recorded result / GPT 6.1 sol
The review states the provisional xenon-opened SDS1 model first. It reconciles the closed X-ray structure and reported HTRF suggestion through Leu movement and modeled ligand fit, while preserving the closed structure as a valid observation. It does not claim proven binding or molecular-glue action.
Read ligand orientation rather than only cavity size
Earns credit
For the xenon-assisted opened SDS1–BTRCP model as a provisional explanation for Nurix accommodation, uses the overlapping ligand ring systems in at least one interface view to argue that the opened SDS1 model accommodates a reference-like position and orientation, a stronger geometric check than saying a cavity exists. Neither preference for this model nor a passing C-010 verdict is required; the other evidence components of C-010 are not prerequisites for this point.
Does not earn credit
the required opened SDS1–BTRCP/Nurix analysis is wrong or missing, or asserts fit from cavity size alone, describes the peptide overlay instead of the ligand, or invents a quantitative pose deviation.
Accepted alternatives
Describing two or more aligned parts of the ligand without a numerical RMSD is sufficient.
Weight: 1
Input evidence
Reference evidence
S079 · Slide 106, fifth bullet
The human says the modeled compound has the same pose and orientation as in beta-catenin/BTRCP reference 6m91.
Recorded result / GPT 6.1 sol
The correct opened SDS1/Nurix context is present, but the review describes only overlapping ligand regions. It does not describe overlapping ring systems or two aligned ligand parts that support a reference-like position and orientation.
Explain why a local opening need not destroy peptide recognition
Earns credit
For the xenon-assisted opened SDS1–BTRCP model as a provisional explanation for Nurix accommodation, connects the magenta/yellow peptide overlap away from the compound entry to preserved peptide placement on BTRCP, explaining why the opened SDS1 model is a local pocket opening rather than a wholly new peptide-binding mode. Neither preference for this model nor a passing C-010 verdict is required; the other evidence components of C-010 are not prerequisites for this point.
Does not earn credit
the required opened SDS1–BTRCP/Nurix analysis is wrong or missing, or claims complete peptide release or a wholly different binding mode, cites only ligand overlap, or assumes identical peptide sequences from the shared backbone path.
Accepted alternatives
A qualitative description of conserved backbone placement is sufficient; exact color-to-peptide assignment is not required.
Weight: 1
Input evidence
Reference evidence
S079 · Slide 106, sixth bullet
The human states that the rest of the peptide is similar and both peptides interact similarly with BTRCP.
Recorded result / GPT 6.1 sol
The review uses cyan receptor-backbone overlap to argue against wholesale receptor rearrangement. It does not connect the peptide overlap away from the entry to preserved peptide placement on BTRCP. Similar receptor folds do not establish that required peptide-recognition inference.
Limit what xenon-assisted opening establishes
Earns credit
For the xenon-assisted opened SDS1–BTRCP model as a provisional explanation for Nurix accommodation, uses the 0.15 M xenon condition to explain that the opened SDS1 model demonstrates possible access under the probing simulation, while how often the pocket opens without xenon remains unmeasured. Neither preference for this model nor a passing C-010 verdict is required; the other evidence components of C-010 are not prerequisites for this point.
Does not earn credit
the required opened SDS1–BTRCP/Nurix analysis is wrong or missing, or treats 0.15 M xenon as a biological requirement for binding, calls it the ligand affinity, or asserts an opening probability under normal conditions from these figures.
Accepted alternatives
A statement that accessibility without the probe remains unknown is sufficient; no new simulation plan is required.
Weight: 1
Input evidence
Reference evidence
S079 · Slide 106, second–third bullets
The human uses xenon to probe potential cryptic pockets, not to measure their normal occupancy.
Recorded result / GPT 6.1 sol
The review identifies the 0.15 M xenon simulation as evidence of possible opening and accommodation. It explicitly leaves the physiological population of the open state without xenon unmeasured.
Keep pocket claims specific to the phosphate state
Earns credit
describes one identifiable interface region whose location or extent differs specifically between the first-pSer and double-pSer SDS1 panels on page 10, using the central cavity as a visual landmark. Connects that geometry comparison to the first-pSer condition of the ARP4 study on page 11 or the SDS1 screening target on page 14, so the modeled pocket claim is not transferred unchanged across phosphate states. A preferred-model decision or a passing C-010 verdict is not required for this source comparison.
Does not earn credit
groups all non-first-pSer states together as different or less extensive, gives colors without locating a geometric difference, mixes the labeled states, or offers only a generic phosphorylation caveat.
Accepted alternatives
For example, the top view has a yellow first-pSer patch immediately left of the central blue cavity that is absent or much reduced in the double-pSer panel; the double-pSer cyan map instead extends above and toward the right of the central cavity. Equivalent accurate comparisons are accepted. No pocket volume or phosphate assignment for the xenon model is required.
Weight: 1
Input evidence
Reference evidence
S079 · Slides 101–102, four state maps and first-pSer pose-study label; slide 105, two target definitions
First-pSer SDS1 has a patch immediately left of the central cavity that differs from double-pSer; the human keeps these maps separate and labels ARP4/screening targets first-pSer.
Recorded result / GPT 6.1 sol
The review correctly identifies the first-pSer study context, but groups the other phosphate states together as having different shapes. It does not locate a specific first-pSer versus double-pSer difference using the central cavity as a landmark.
Keep compound compatibility separate from activity prediction
Earns credit
names one retained pose from each listed ARP4 group within the same peptide/pocket condition, using compound and complex identifiers. Explains why this within-condition cross-group retention does not separate activity classes, then distinguishes those ARP4 observations from the separate Nurix opened-interface overlay and its structural accommodation claim. A preferred-model decision or a passing C-010 verdict is not required for this source comparison.
Does not earn credit
merely asserts cross-group retention, pools different peptide/pocket conditions for the contrast, assigns undocumented active/inactive group labels, omits pose identifiers, or transfers ARP4 retention to Nurix activity.
Accepted alternatives
For SDS1 pocket 2, group 2/216/226/253 can be represented by 0002 complex1 or 0216 complex1; group 65/85/233/252 by 0065 complex1, 0085 complex1, 0233 complex1 or 0252 complex1. SDS3 examples from each group in that single condition are also accepted if both pose identifiers are correct. The source lists groups without mapping each to an activity label.
Weight: 1
Input evidence
Reference evidence
S079 · Slides 102, 104 and 106
The separate source lists each include retained poses within one condition, such as 0002 complex1 and 0065 complex1 in SDS1 pocket 2. The record treats ARP4 retention and Nurix modeling as separate comparisons.
Recorded result / GPT 6.1 sol
Within SDS1 pocket 2, the review names retained 0002 complex2 and 0065 complex2 from the two listed groups. It explains why retention does not establish activity separation, avoids assigning undocumented activity labels, and distinguishes these ARP4 results from the separate Nurix accommodation model.
Leave small-molecule affinity unresolved by structural fit
Earns credit
For the xenon-assisted opened SDS1–BTRCP model as a provisional explanation for Nurix accommodation, explains that the opened SDS1–Nurix fit supports physical compatibility but does not establish how tightly the small molecule binds; links this limit to the absence of quantitative binding data in the displayed records, rather than treating a docking score as Kd. Neither preference for this model nor a passing C-010 verdict is required; the other evidence components of C-010 are not prerequisites for this point.
Does not earn credit
the required opened SDS1–BTRCP/Nurix analysis is wrong or missing, or reports an invented SDS1–Nurix Kd, claims high affinity from the pose or score alone, or names an assay without explaining which inference is still unsupported.
Accepted alternatives
Affinity can be described as binding strength; no specific assay or experiment order is required.
Weight: 1
Input evidence
Reference evidence
S079 · Slide 80, third bullet; slide 106, first and fifth bullets; slide 110, final line
The human uses structural contacts as useful evidence and names compound affinity as a separate measurement.
Recorded result / GPT 6.1 sol
The review treats the opened SDS1–Nurix fit as physical accommodation and explicitly leaves affinity unmeasured in the displayed records. It does not turn a docking score into a binding-strength measurement.
Leave protein-contact stabilization unresolved by small-molecule binding
Earns credit
For the xenon-assisted opened SDS1–BTRCP model as a provisional explanation for Nurix accommodation, explains that the opened SDS1 model can accommodate Nurix but does not show that Nurix strengthens SDS1 binding to BTRCP; identifies peptide–BTRCP affinity with versus without Nurix as the comparison needed to support that molecular-glue claim, distinct from merely measuring Nurix binding. Neither preference for this model nor a passing C-010 verdict is required; the other evidence components of C-010 are not prerequisites for this point.
Does not earn credit
the required opened SDS1–BTRCP/Nurix analysis is wrong or missing, or calls accommodation proof of stabilization, uses only Nurix occupancy to establish a stronger protein contact, substitutes beta-catenin or SDS3 for the SDS1 comparison, or offers repeat-with-controls advice without the paired affinity inference.
Accepted alternatives
A stronger interaction may be described as lower peptide Kd or increased bound fraction at matched concentrations; neither outcome is claimed to have been observed.
Weight: 1
Input evidence
Reference evidence
S079 · Slide 106, structural explanation; slide 110, final two lines
The human separates compound binding from the peptide-affinity comparison needed to assess stabilization.
Recorded result / GPT 6.1 sol
The review correctly leaves stabilization unproven, but never identifies the needed comparison of SDS1–BTRCP affinity with versus without Nurix. Merely listing affinity and stabilization as unmeasured does not distinguish that comparison from measuring Nurix binding itself.