Path sampling challenges in large biomolecular systems: RETIS and REPPTIS for ABL-imatinib kinetics

An Ghysels; Daniel T. Zhang; Enrico Riccardi; Titus S. van Erp; Wouter Vervust

REVIEW 3 major objections 6 minor 110 references

Path sampling challenges in large biomolecular systems: RETIS and REPPTIS for ABL-imatinib kinetics

T0 review · 3 major / 6 minor · reviewed 2026-08-16 · deepseek-v4-flash

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Pith's one-line read This paper claims that for imatinib dissociation from ABL kinase, a one-dimensional order parameter cannot resolve the metastable states and parallel pathways, so RETIS and REPPTIS do not converge to dependable kinetics.

desk verdict An honest negative result that tells the path-sampling community what it needs to hear, even though the causal story is tangled up with initialization choices. read the letter →

arxiv 2504.14722 v1 pith:L27EMZTH submitted 2025-04-20 physics.bio-ph cond-mat.softcond-mat.stat-mechphysics.chem-phphysics.comp-ph

Wouter Vervust , Daniel T. Zhang , Enrico Riccardi , Titus S. van Erp , An Ghysels This is my paper · ORCID

classification physics.bio-phcond-mat.softcond-mat.stat-mechphysics.chem-phphysics.comp-ph

keywords pathsamplingtransitioninterfaceimatinibABLkinasedrugresidencetimereactioncoordinatemetastablestatesrareeventsimulation

verification ladder T0 review T1 audit T2 compute T3 formal

The pith

A machine-rendered reading of the paper's core claim, the machinery that carries it, and where it could break.

The reading

This paper reports a systematic attempt to compute imatinib dissociation rates from wild-type and seven mutated ABL kinase domains using replica exchange transition interface sampling (RETIS), its partial-path variant (REPPTIS), and the asynchronous infinite-swap variant ($\infty$RETIS). None of the simulations converged to a reliable rate constant. The authors attribute the failure to the use of a one-dimensional order parameter $\lambda$, defined as the distance from the drug to its average bound position, which cannot separate the metastable states and orthogonal barriers that give rise to parallel unbinding pathways. If this diagnosis is right, it matters practically: standard TIS-family path sampling, initialized by steered molecular dynamics, is not yet dependable for predicting drug residence times in large biomolecular systems. The paper also shows that even a hybrid $\infty$RETIS–REPPTIS reconstruction yields a rate more than ten orders of magnitude below experiment, reinforcing the need for multidimensional reaction coordinates and better initialization.

What carries the argument

The central object is the interface-ensemble construction of TIS-family methods: states $A$ and $B$ are separated by hypersurfaces of constant $\lambda$, and the rate is built from a flux $f_A$ times a product of local crossing probabilities $P_A(\lambda_{i+1}|\lambda_i)$. RETIS adds replica exchange between the ensembles, $\infty$RETIS extends this to asynchronous infinite swapping, and REPPTIS cuts paths short at neighboring interfaces, introducing a Markovian approximation. The argument turns on what this machinery cannot see: barriers and metastable states that lie orthogonal to $\lambda$ confine paths to a single channel, produce extremely long or one-phase-point paths, frustrate the swap moves, and leave the local crossing probabilities zero in 'problematic' ensembles. In short, the mechanism that carries the paper's argument is the mismatch between a one-dimensional progress variable and the genuinely multidimensional dissociation network.

What would settle it

Run the same RETIS/REPPTIS protocol with initial paths taken from a converged long unbiased dissociation trajectory (or from a multidimensional collective-variable map) for wild-type ABL, and compare with the experimental range $10^{-4}$–$10$ s$^{-1}$; if the rate converges to experiment, the paper's claim that one-dimensional $\lambda$ cannot resolve the kinetics is falsified, whereas repeated failure across independent initialization strategies would confirm it.

Watch

Extended reading notes

Core claim

The central claim is that for ABL-imatinib dissociation, a one-dimensional order parameter $\lambda$ (distance between imatinib's center of mass and its average bound position) cannot resolve the metastable states and parallel dissociation channels, and that this is why RE(PP)TIS and $\infty$RETIS fail to converge. In the paper's own words, the separation of timescales introduced by these states 'might fundamentally not be resolvable by a one-dimensional $\lambda$-based approach.' The evidence offered is the pattern of stuck path ensembles near the binding pocket, the dependence of the crossing-probability profile on poorly sampled orthogonal degrees of freedom such as the Y253–N322 hydrogen bond in the wild type, and the large discontinuity in the $\infty$RETIS crossing probability. The authors do not conclude that TIS-family methods are useless; they conclude that as currently initialized and moved, they are not yet a reliable tool for residence-time prediction in such high-dimensional systems.

Load-bearing premise

The paper's diagnosis assumes that the initial paths produced by 50 ns steered molecular dynamics are representative enough of true unbiased dissociation pathways, so that the failure to converge reflects the landscape rather than bad starting points; the authors themselves suspect this is false for wild-type ABL, whose steered path was pulled along a barrier orthogonal to $\lambda$.

Editorial extensions

If this is right

If the diagnosis is correct, standard RETIS and REPPTIS runs on a simple distance order parameter cannot yet supply trustworthy $k_{\mathrm{off}}$ values for kinase–drug systems.
Converged-looking error bars can be misleading: for E255V and T315I the block-averaging errors were modest although many ensembles had failed, so error estimates cannot substitute for checking per-ensemble crossing statistics.
A hybrid $\infty$RETIS inner region plus REPPTIS outer region remains insufficient; the paper's combined wild-type estimate is $1.98\times 10^{-18}$ s$^{-1}$, more than ten orders below the experimental range.
For the six mutants whose initial paths exit under the $\alpha$C-helix, even a converged simulation would likely report only that channel's rate, not the net rate over all pathways.
Future work would need multidimensional or learned collective variables, and moves that transfer orthogonal exploration into the path ensembles, before drug-residence-time prediction can rely on these methods.

Reading between the lines

Editorial extensions of the paper, not claims the author makes directly.

An implicit testable consequence: if the orthogonal barriers are generic, then other one-dimensional rare-event estimators (milestoning with a single progress variable, one-dimensional metadynamics) applied to ABL-imatinib should show similar channel-locking artifacts; comparing committor distributions along $\lambda$ would expose them.
The paper's negative result suggests a practical screening order: first use cheap biased sampling to map metastable states and exit channels, then define a network or path collective variable from that map before spending compute on path sampling.
Because the wild-type dominant hinge route requires breaking the Y253–N322 hydrogen bond orthogonal to $\lambda$, mutation effects on that bond's stability could be read out from equilibrium fluctuations alone, giving a fast qualitative predictor of kinetic resistance that path sampling can later refine.
A direct extension would replace the single distance with a learned low-dimensional coordinate and re-run the same $\infty$RETIS/REPPTIS pipeline; the paper's claim predicts convergence would improve, and that is a testable benchmark.

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Editorial analysis

A structured set of objections, weighed in public.

Desk editor's note, referee report, and a circularity audit.

Desk Editor's Note

read the letter

Colleague, read the Vervust et al. paper on RETIS/REPPTIS for ABL-imatinib. Short version: it's a genuinely useful negative result, and it's more honest than most positive papers in computational biophysics. The authors applied three flavors of TIS-family path sampling to imatinib unbinding, got no converged kinetics, and said so plainly. They explicitly label their rate estimate 10 orders of magnitude too low, call their own error bars overoptimistic, and publish configurations and code. That's the right way to report a failure.

What's new: first application of RETIS, REPPTIS, and ∞RETIS to this specific system; the asynchronous REPPTIS implementation and the trajectory-based λ calculator are real technical improvements, and the detailed per-ensemble diagnostics (path lengths, acceptance counts, crossing probabilities) give future method developers something to bite on. The paper also correctly situates itself against milestoning and infrequent metadynamics work that already concluded a 1D coordinate is insufficient for this system, so the headline message isn't new, but the direct evidence from TIS-family methods is.

The soft spot is exactly what the stress-test note says, and what the authors themselves admit: the WT initial path came from steered MD that pulled under the αC-helix, while literature (Shekhar et al.) finds the hinge route dominates after Y253–N322 hydrogen-bond breaking. If the starting path isn't on the dominant pathway, the observed non-convergence could be an artifact of initialization rather than a fundamental limit of 1D λ. The paper's own wording—'might fundamentally not be resolvable'—is appropriately hedged, but that means the central claim is conditional. The fixed protocol choices (46 interfaces, 4 ns max path length for all variants) add further confounds. None of this makes the paper wrong; it makes it a case study rather than a proof.

Who is this for: anyone running TIS-family simulations on large biomolecular systems, and method developers thinking about order parameters and initialization. It's not a general biochemistry reader's paper.

I'd send this to peer review. It's a well-executed negative result with reproducible data and honest analysis. The reviewers should push the authors to separate initialization-confounded failures from intrinsic landscape limitations, but that's a revision, not a rejection. I'd probably cite it myself when discussing practical limits of TIS methods.

Referee Report

3 major / 6 minor

Summary. This paper reports an attempt to compute imatinib dissociation kinetics from wild-type and seven mutant ABL kinase domains using RETIS, REPPTIS, and ∞RETIS, with a one-dimensional distance order parameter λ (Eq. 2) and 46 interfaces. The central empirical result is negative: none of the REPPTIS simulations converges to a reliable rate, many path ensembles have zero or near-zero local crossing probabilities, and the WT ∞RETIS run over λ∈[1,6] Å shows discontinuous crossing probability profiles despite improved sampling. The authors attribute the failure to long-lived metastable states, barriers orthogonal to λ, parallel dissociation pathways, and non-representative steered-MD initial paths, and they propose improved initialization, multidimensional order parameters, and advanced shooting moves as remedies. The paper is explicitly transparent about the limitations: the single reported combined rate of 1.98×10^-18 s^-1 is labeled as more than ten orders of magnitude below experiment and is accompanied by a warning that the error estimates are overoptimistic for unconverged simulations.

Significance. If the negative finding is robust, this is a valuable case study for the path-sampling and drug-discovery communities: it documents that RE(PP)TIS-family methods, as currently initialized and parameterized, cannot yet be used as a black box for residence-time prediction in a large biomolecular system. The manuscript is unusually transparent: no converged rate is claimed, problematic ensembles are tabulated, and configuration/topology files are deposited on Zenodo. The main open question is whether the failure demonstrates a fundamental limitation of one-dimensional order parameters for this system or, more narrowly, a failure of the specific λ, initialization, and protocol settings chosen here. Because the authors themselves suspect that the WT initial path was not representative of the dominant hinge-route pathway, the stronger 'fundamental' interpretation is not yet established. The paper's practical value lies less in the rate estimates than in the detailed diagnostics and the clear agenda for methodological development.

major comments (3)

[Results, 'Causes of REPPTIS sampling issues'; Discussion] The central claim that a one-dimensional λ cannot resolve the metastable states and parallel pathways of ABL-imatinib is not yet separable from the initialization confound you raise. In 'Causes of REPPTIS sampling issues' you write that 'the initial path of WT ABL was not representative for the dominant reaction pathway,' and in the Discussion you note that the WT steered-MD path escaped under the αC-helix whereas Shekhar et al. (Ref. 80) found the dominant WT route via the hinge after breaking the Y253–N322 hydrogen bond, a coordinate orthogonal to λ. Because the REPPTIS paths in the problematic ensembles are short (about 20 phase points, roughly 0.8 ps) and successive paths are correlated through the same reaction channel, a non-representative start can produce exactly the observed zero local crossing probabilities even if a one-dimensional λ would suffice for the true dominant route. I ask for a concrete test: initialize REPPTIS from a hinge-route path or from several diverse steered paths and compare the local crossing probabilities; alternatively, analyze the existing WT trajectories for the Y253–N322 hydrogen bond to evidence whether the hinge channel is present at all in the sampled path ensemble. Until one of these tests is provided, the wording in the Abstract and Conclusion should retrench from a landscape-based failure to 'not resolvable with the specific λ, initial paths, and protocol used here.'
[Results, '∞RETIS simulations'] The evidence presented for the 'fundamentally not resolvable' statement in the ∞RETIS results is weaker than the claim. The discontinuities in Fig. 7A are explained in the text as undersampling: the first nine positive ensembles have average path lengths of one phase point, and the λ≥4.5 Å region has fewer than 100 accepted paths (Fig. 8A). These are practical sampling limitations of this particular run (frame-saving rate n_subcycles = 500, maximum path length 100 ns, and the chosen interface spacing), not a demonstrated failure of the order parameter to separate metastable states. The long path lengths for λ beyond 6 Å show that transitions are rare and slow, but they do not exclude a better-chosen one-dimensional coordinate, such as the contact-map parameter you propose in the Discussion, from resolving the relevant states. Please either soften the 'fundamentally' language to a hypothesis, or add supporting analysis (for instance, committor estimates for λ, or a test on one variant with an alternative 1D coordinate).
[Discussion] The Discussion states that 'a one-dimensional order parameter is fundamentally not sufficient' for ABL-imatinib dissociation. As written, this reads as a conclusion of the present work, but the supporting evidence in that paragraph comes from Refs. (79) and (80) (milestoning with average Voronoi connectivity 2.93 and a 5-dimensional metadynamics model), not from the simulations reported here. Your own data demonstrate non-convergence for one specific distance coordinate with one initialization protocol, which is an important but narrower result. Please mark the fundamental-insufficiency statement explicitly as a literature-supported hypothesis, or provide additional evidence from this study to support it.

minor comments (6)

[Table 2] The variant label 'Y53F' should be 'Y253F' to be consistent with Table 1 and the text.
[Causes of REPPTIS sampling issues] The text refers to 'the E225V and T315I rates'; this should be 'E255V'.
[References] References 23 and 24 appear to be the same article (Bolhuis and Swenson, Adv. Theory Simul. 4:2000237, 2021); please merge or remove the duplicate.
[Results, '∞RETIS simulations'] The sentence 'This means that, for these 1-phase point paths, the configuration remains identical as only the momenta are modified' is confusing; a one-phase-point path has no internal dynamics, so please rephrase to say that shooting from such a path generates a new trajectory from the same configuration with new momenta.
[Methods, Pulling simulations] The claim that the pulling force was 'non-directional' is not self-evident because the moving restraint on λ exerts a force along the instantaneous direction of the ligand displacement vector; please clarify the intended meaning or provide quantitative support for this statement.
[Code availability] The statement that the custom version of ∞REPPTIS is 'available on request' is weaker than the rest of the reproducibility package (Zenodo deposition of configurations); please deposit the code in a public repository as well.

Circularity Check

0 steps flagged · score 0.0 of 10

No circularity: the paper is a self-contained failure report with no fitted-input-as-prediction or load-bearing self-citation.

full rationale

This paper reports non-convergence of RETIS/REPPTIS simulations for ABL-imatinib dissociation and hypothesizes that a one-dimensional order parameter is insufficient. There is no fitted parameter that is then renamed as a prediction: the experimental k_off values are used only as external benchmarks, not as inputs to any calibration. The methodological choices (46 interfaces, 4 ns maximum path length, steered-MD initial paths, COM-distance order parameter) are stated inputs, not quantities tuned to reproduce the target rate. The combined ∞RETIS+REPPTIS rate estimate is an explicitly ad hoc construction, not a derivation that reduces to its own inputs. The central claim that metastable states and orthogonal barriers limit a 1D-λ description is presented as a hypothesis ('might fundamentally not be resolvable') and is corroborated by independent external studies (Refs. 79, 80), not by self-citation. Self-citations to PyRETIS and ∞RETIS concern software and method provenance and are not load-bearing for the scientific conclusion. The paper is honestly self-critical about the initialization confound, which is a correctness risk, not circularity. No step reduces to its inputs by construction, so the circularity score is 0.

Assumptions & free parameters 7 free parameters · 5 assumptions · 0 invented entities

The central claim rests on hand-chosen numerical inputs such as interface spacing, path length cutoffs, pulling parameters, saving frequency, and move mix, and on the assumptions that the force field is accurate, that steered-MD initial paths are representative, and that the Markovian approximation of REPPTIS is valid for λ. No new physical entities are introduced. The paper does not fit target rates; the experimental comparison is external. The main diagnostic conclusion depends on the weakest assumption, the representativeness of initial paths.

free parameters (7)

Order parameter λ = COM distance to r_bound_COM; λ_A=1 Å, λ_B=38 Å (REPPTIS) or 6 Å (∞RETIS)
Chosen to track separation of imatinib from the bound pose; its definition constrains the entire path sampling analysis.
Interface set = 46 interfaces (REPPTIS); 51 interfaces spaced 0.1 Å for WT ∞RETIS
Interface placement was estimated from rough umbrella sampling (Fig. S6); the number and placement directly set local crossing probabilities.
Maximum path length = 4 ns (REPPTIS), 100 ns (∞RETIS)
Practical cutoff for path storage and MC acceptance; the authors note paths hitting the maximum were rare for REPPTIS.
Steered MD pulling parameters = 50 ns, v=0.76 Å/ns, moving restraint κ=250 kJ mol^-1 nm^-2, Cα restraints κ=5000 kJ mol^-1 nm^-2
Generate the initial paths; pulling velocity and force were manually adjusted to avoid protein-opening artifacts.
Frame-saving rate (n_subcycles) = REPPTIS: n_subcycles=20 (40 fs); ∞RETIS: n_subcycles=500 (1 ps)
Controls resolution of paths and number of shooting points; the paper attributes slow decorrelation near λ≈1.9 Å to the 1 ps saving frequency.
Swap move probability = 25% replica exchange, 75% shooting
MC move mix in REPPTIS; replica exchange acceptance is low, which the paper identifies as a bottleneck.
Rigid Cα set = variant-specific sets from 50 ns equilibrium RMSF (Table S1)
Used to align frames for the order parameter and for pulling restraints; derived from short equilibration simulations.

assumptions (5)

standard math Converged TIS and RETIS ensembles reconstruct exact kinetics; PPTIS/REPPTIS reconstruct approximate kinetics under a Markovian assumption on crossing probabilities.
Basis of the whole analysis, taken from Refs. 25, 29, 30, 32, 33; used in the section 'RETIS and REPPTIS theory'.
domain assumption The Markovian approximation in REPPTIS holds for the chosen distance order parameter λ.
REPPTIS combines short path segments assuming memory loss between interfaces; the authors later state its validity depends on the order parameter (Discussion).
ad hoc to paper Steered MD initial paths are representative of unbiased dissociation pathways.
Initial path for every variant comes from one 50 ns pulling run; the Results acknowledge the WT path may not be representative.
domain assumption The force field (CHARMM36m, TIP3P, imatinib parameters from Ref. 63) accurately describes the relevant interactions.
Used throughout; the 10-orders-of-magnitude gap to experiment is attributed primarily to sampling, not force field, but this is not tested.
ad hoc to paper A single distance coordinate λ is an adequate reaction coordinate for the TIS interface ensembles.
All simulations define interfaces by λ (Eq. 2); the paper's conclusion is that this assumption fails.

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Cite this review

Pith. "Pith review of Path sampling challenges in large biomolecular systems: RETIS and REPPTIS for ABL-imatinib kinetics." pith.science (2026). https://pith.science/paper/L27EMZTH

@misc{pith2026250414722,
  author       = {Pith},
  title        = {Pith review of: Path sampling challenges in large biomolecular systems: RETIS and REPPTIS for ABL-imatinib kinetics},
  year         = {2026},
  howpublished = {\url{https://pith.science/paper/L27EMZTH}},
  note         = {Machine review of arXiv:2504.14722}
}

read the original abstract

Predicting the kinetics of drug-protein interactions is crucial for understanding drug efficacy, particularly in personalized medicine, where protein mutations can significantly alter drug residence times. This study applies Replica Exchange Transition Interface Sampling (RETIS) and its Partial Path variant (REPPTIS) to investigate the dissociation kinetics of imatinib from Abelson nonreceptor tyrosine kinase (ABL) and mutants relevant to chronic myeloid leukemia therapy. These path-sampling methods offer a bias-free alternative to conventional approaches requiring qualitative predefined reaction coordinates. Nevertheless, the complex free-energy landscape of ABL-imatinib dissociation presents significant challenges. Multiple metastable states and orthogonal barriers lead to parallel unbinding pathways, complicating convergence in TIS-based methods. Despite employing computational efficiency strategies such as asynchronous replica exchange, full convergence remained elusive. This work provides a critical assessment of path sampling in high-dimensional biological systems, discussing the need for enhanced initialization strategies, advanced Monte Carlo path generation moves, and machine learning-derived reaction coordinates to improve kinetic predictions of drug dissociation with minimal prior knowledge.

Figures

Figures reproduced from arXiv: 2504.14722 by the authors.

**Figure 1.** Inactive (A, PDB 6NPV (45)) and active (B, PDB 6XR6 (46)) conformations of the ABL kinase domain. C: Close up of the binding pocket in the inactive state. Imatinib binds to the inactive state, where the aspartate residue points outwards of the binding pocket. D: Close up of the binding pocket in the active state. In the active state, the aspartate residue points inwards of the binding pocket. In A and B, the dashed … view at source ↗

**Figure 3.** Order parameter 𝜆 (Eq. 2) for equilibrium MD trajectories of the ABL variants. As the pulling was done slowly, and 𝜆 is defined as the distance to the average bound state, it is expected that the pulling force was non-directional. Six of the variants escaped via a pathway under the 𝛼C-helix, while the Q252H and F359V variants had imatinib escape via a pathway under the P-loop (Text S3, Fig. S3). The evolution of the… view at source ↗

**Figure 4.** Pulling simulations of 50 ns, for each variant. [PITH_FULL_IMAGE:figures/full_fig_p006_4.png] view at source ↗

Figures from the paper (4 more)

**Figure 5.** Figure 5: Crossing probability profile 𝑃𝐴(𝜆𝑖 |𝜆𝐴) for the ABLimatinib systems (A) over the entire 𝜆 ∈ [1, 38] Å range and (B) zoomed in on the 𝜆 ∈ [1, 6] Å range. Profiles related to the REPPTIS simulations (lines with X-markers for each interface) have artificially assigned lo…

**Figure 6.** Figure 6: Analysis of REPPTIS simulations with 46 ensembles for each variant. Ensemble index [PITH_FULL_IMAGE:figures/full_fig_p009_6.png]

**Figure 7.** Figure 7: WT ABL ∞RETIS results, where the first 5000 accepted paths were discarded to reduce initialization effects. A: The crossing probability profile 𝑃𝐴(𝜆|𝜆𝐴) of Eq. 1. Arrows indicate visible discontinuities. B: The running estimate of the global crossing probability 𝑃𝐴(𝜆𝐵|…

**Figure 8.** Figure 8: Sampling analysis of the ∞RETIS WT ABL simulation. All shooting cycles are included in the analysis, i.e. paths generated by the zero swap move in [0 − ] and [0 + ] are excluded. Ensemble index 1 corresponds to [0 − ], ensemble index 2 to [0 + ], ensemble index 3 to […

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