Conformational convergence
Tracks whether protein and ligand coordinates settle into a stable ensemble or continue to drift.
Look for a sustained plateau
Molecular dynamics stability profiling
PROTAC Binding Stability Analysis by MD
A static ternary-complex pose can look perfect and still fall apart in solution. We challenge your protein–PROTAC–E3 ensemble with replicate molecular dynamics and turn trajectory metrics into a clear read on which designs stay bound.
RMSD & RMSFRadius of gyrationH-bond occupancyMM/GBSA energy
What we measure
See whether your PROTAC complex stays together in motion
We combine structural, contact, and energetic readouts to distinguish a complex that merely forms from one that remains productively assembled throughout the trajectory.
Local flexibility
Locates mobile residues, weakly anchored interface regions, and linker segments that may need redesign.
Flag excessive interface motionGlobal compactness
Tests whether the ternary assembly maintains a compact architecture rather than gradually opening or separating.
Check for consistent packingInteraction occupancy
Measures how consistently key hydrogen bonds anchor the warhead, recruiter, and protein interfaces.
Prioritize persistent contactsInterface persistence
Shows which protein–protein and protein–PROTAC contacts survive across the simulation ensemble.
Verify a durable interfaceRelative energy ranking
Uses ensemble-based MM/GBSA estimates to compare linker or recruiter designs under a consistent protocol.
Rank candidates comparativelyA stability report your team can read at a glance
Each complex is summarized as a compact stability readout: how converged the ensemble is, where it flexes, and which interactions hold. The panel below is illustrative of a single representative system.
RMSD (backbone)
1.3 ± 0.2 Å
Stable basin after 80 ns
H-bond occupancy
82%
Warhead + recruiter anchors
Radius of gyration
27.4 ± 0.6 Å
Compact, persistent assembly
Relative ΔG (MM/GBSA)
-12.6 kcal/mol
Ranked vs linker series
Image placeholderRecommended asset: side-by-side RMSD and RMSF plots for a representative PROTAC ternary complex, with key interface residues annotated.
When to use this service
Use MD when a static structure is not enough
Choose among similar PROTACs
Compare a matched series before committing to synthesis or broader assays.
- Linker length or composition
- Attachment-point variants
- Warhead or recruiter changes
Check a new ternary pose
Test whether a docking or AI-generated pose remains physically plausible after solvation and relaxation.
- Pose retention
- Interface rearrangement
- Early dissociation risk
Explain mixed assay results
Investigate why compounds with similar binary affinity show different ternary binding or degradation behavior.
- Cooperativity clues
- Lost protein contacts
- Linker strain
Plan the next design round
Locate flexible or weakly anchored regions and turn them into specific design hypotheses.
- Linker redesign
- Recruiter orientation
- Follow-up assay choice
How it works
How we test binding stability step by step
The workflow checks the starting model, runs independent simulations, and links the combined evidence to a practical design decision.
Request an MD ScopePrepare the ternary system
Build and solvate the protein–PROTAC–E3 complex, assign protonation states and ligand topologies, and validate the input geometry.
Equilibrate and stabilize
Run staged energy minimization and equilibration with progressively released restraints to reach a production-ready state.
Run replicate production
Execute independent production trajectories with different initial velocities to sample the ensemble rather than one path.
Compute stability metrics
Extract RMSD, RMSF, Rg, H-bond occupancy, contact persistence, and MM/GBSA estimates across all replicates.
Interpret and recommend
Connect stability to design: which linkers, attachment points, or recruiters hold, and what should be tested next.
Study options
Choose the level of analysis that fits your decision
Is this pose likely to hold?
For one complex when you need an early stability signal before deeper work.
- Best for: a new modeled pose or feasibility check
- Includes: system QC, replicate MD, core stability metrics
- Decision: continue, remodel, or test an alternative pose
Which candidate looks more stable?
For a matched set of PROTACs evaluated under consistent conditions.
- Best for: linker, attachment-point, or recruiter series
- Includes: shared protocol, comparative metrics, relative energy ranking
- Decision: prioritize candidates and explain the rank order
Why does stability differ?
For a deeper investigation that connects dynamics with ternary binding or degradation data.
- Best for: conflicting assays or lead optimization
- Includes: interface networks, state clustering, focused energy analysis
- Decision: identify a design mechanism and plan validation
Trust a pattern seen in several simulations
Single simulations can mislead. We report each replicate separately, check whether the results settle over time, and show the spread across runs so the conclusion does not depend on one favorable trajectory.
ReplicatesIndependent velocity-seeded runs
ConvergencePlateau and drift diagnostics
PersistenceH-bond and contact occupancy
RankingRelative ΔG across designs
Compare candidates with a clear stability grade
We group designs by how consistently the simulations support sustained binding. The grade is a project-specific summary, not a universal experimental score.
AConverged, compact, persistent interactions across all replicates
BStable with one flexible linker or interface region to watch
CIntermittent binding with partial interface loss in some replicates
DUnstable: dissociation or persistent strain across trajectories
What we need to start your study
Send what you already have. Missing pieces can often be modeled, but knowing what is experimental and what is predicted helps us set the right confidence level.
- Target and E3 ligase structures, models, or identifiers
- PROTAC structure with attachment atoms clearly marked
- A ternary pose, if one is already available
- Known binary, ternary, or degradation data
- The candidate comparison and decision you need to make
Know what the results can—and cannot—tell you
We check structure quality, protonation, ligand parameters, equilibration, replicate agreement, and sampling before assigning a stability conclusion.
- Can reveal drift, flexibility, contact loss, and relative stability
- Can explain structural differences within a matched candidate series
- Cannot guarantee cellular degradation or clinical performance
- Cannot remove uncertainty from a poor starting pose or limited sampling
How we handle uncertainty: assumptions, failed quality checks, model dependence, and non-converged results are stated plainly in the report rather than hidden inside a single score.
What you receive
Get files, comparisons, and a clear next step
Decision-focused conclusion
A plain-language answer to the project question, with confidence and limitations stated up front.
Simulation dataset
Prepared systems, replicate trajectories, run parameters, and file annotations for traceability.
Stability metric report
RMSD, RMSF, Rg, SASA, H-bond occupancy, and contact persistence for each replicate.
Figures and interaction maps
Comparison plots, representative structures, contact maps, and annotated regions of concern.
Relative binding-energy ranks
MM/GBSA estimates across suitable designs, with convergence checks and interpretation caveats.
Design and assay recommendations
Candidate priorities, linker or attachment-point hypotheses, controls, and useful next experiments.
Published data
What published studies tell us about PROTAC stability
Study [1] · Three-body MD
Molecular dynamics reveals the three-body energetics of PROTAC complexes
Li W, Zhang J, Guo L, Wang Q. Journal of Chemical Information and Modeling. 2022;62(3):523–532.Using MD and MM/GBSA, the authors modeled the three-body nature of PROTAC complexes and showed that including protein–protein interactions improves pose evaluation, with calculated energies correlating with experimental affinity trends.
Service implication: stability analysis always includes the induced protein–protein interface, not just binary ligand binding, when scoring the ternary ensemble.
MD → interface → rankingOriginal schematic
Ternary ensembleBuild target–PROTAC–E3 complexes from binary poses.
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MD + MM/GBSASample three-body dynamics including protein–protein contacts.
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Stability rankingRank designs by sustained geometry and energetic support.
Dynamic stabilityInterface energyCooperativityPose ranking
Study [2] · Interface & degradation
Ternary affinity and cooperativity connect structural stability to degradation
Wurz RP, Rui H, Dellamaggiore K, et al. Nature Communications. 2023;14:4177.Across VHL-recruiting degraders, ternary-complex affinity and cooperativity correlated with degradation potency and rate, and a structural workflow linked buried interface area to measured ternary binding affinity.
Service implication: stability descriptors are interpreted alongside interface area and any experimental ternary data, so molecular geometry is tied to degradation behavior rather than treated in isolation.
Structure → affinity → outcomeOriginal schematic
PROTAC variantsVary warhead, linker, and recruiter across a matched series.
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Ternary attributesMeasure affinity and cooperativity; model interface area.
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Degradation designRelate structural stability to potency and degradation rate.
Ternary affinityCooperativityInterface areaDegradation rate
References
- Li W, Zhang J, Guo L, Wang Q. Importance of Three-Body Problems and Protein-Protein Interactions in Proteolysis-Targeting Chimera Modeling: Insights from Molecular Dynamics Simulations. J Chem Inf Model. 2022;62(3):523–532. https://doi.org/10.1021/acs.jcim.1c01150
- Wurz RP, Rui H, Dellamaggiore K, et al. Affinity and cooperativity modulate ternary complex formation to drive targeted protein degradation. Nat Commun. 2023;14:4177. https://doi.org/10.1038/s41467-023-39904-5
Project questions
Common questions before you start
A strong MD project starts by defining which stability question will drive the next design decision.
We compute RMSD, RMSF, radius of gyration, solvent-accessible surface area, hydrogen-bond occupancy, and residue contact persistence, plus MM/GBSA binding-energy estimates where appropriate. These are reported per replicate with convergence diagnostics.
Timescales are chosen per system, typically hundreds of nanoseconds with multiple replicates, and are extended when slow conformational transitions or convergence require it. We report the rationale for every timescale used.
Yes. Independent replicates with different initial velocities are essential to distinguish a genuinely stable complex from one that only appears stable in a single trajectory. Conclusions are drawn across the full replicate ensemble.
No single metric guarantees cellular degradation. MD stability indicates whether the ternary complex persists and where it flexes. It is combined with geometry, lysine accessibility, and experimental data to prioritize designs rather than claim degradation.
A ternary-complex structure or model (or the components to build one), ligand topologies, and any known binding or degradation data. We can build and prepare the system if you provide the target, E3 ligase, and PROTAC chemistry.
Yes. A matched-series study can compare linker lengths, attachment points, warheads, or E3 recruiters under the same simulation and analysis settings. We emphasize relative ranking and explain when candidates are too different for a direct comparison.
We can begin from suitable target and E3 structures or models, place the PROTAC, generate candidate ternary poses, and select plausible starting systems for MD. Model uncertainty is documented and carried into the final interpretation.
Start a project
Find out which PROTAC complex is more stable
Share the target, E3 ligase, and PROTAC structures or chemistry. CD ComputaBio will propose an MD scope with suitable sampling, replicates, and metrics for the decision you need to make. Related services: PROTAC Molecular Dynamics Service, PROTAC Binding Kinetics Analysis, AI PROTAC Ternary Complex Modeling.
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