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This research addresses a critical bottleneck in biomolecular structure prediction by introducing lightweight, closed-form projection operators that enforce physical validity during the inference phase of diffusion models. Unlike previous methods requiring costly retraining or heavy physics-informed potentials, this approach corrects atomic clashes and geometric distortions without altering the underlying model weights or significantly increasing computational overhead. It offers a practical, model-agnostic solution for ensuring that high-accuracy predictions from systems like AlphaFold 3 are also physically realistic.
Inference-Time Projection for Physically Valid Biomolecular Diffusion Models
arXiv:2610.07037v1 Announce Type: cross Abstract: AlphaFold 3-style cofolding models predict biomolecular complexes with high structural accuracy, yet a large fraction of their outputs are physically invalid: chains overlap at interfaces, ligand bond lengths and angles are distorted, rings are non-planar, and stereocentres are inverted. Current approaches either steer the sampler with physics-informed potentials, which multiplies sampling cost and memory overhead making inference impossible on large complexes, or finetune the model, costing time and tying the fix to one architecture. We observe that, unlike structural accuracy, physical validity is fully verifiable at inference time from quantities the sampler already holds. We therefore treat physical validity as a constrained inference problem and introduce two closed-form projection operators applied to the diffusion model's denoised clean-coordinate estimate, $\hat{x}_0$: an inter-chain van der Waals projection that pushes apart the most severely clashing atom pairs, and a ligand distance-geometry projection that restores bond lengths, angles, internal contacts, planarity and chirality. Both operators are local, sparse and displacement-capped, require no network evaluations, gradients or importance sampling, and leave the denoiser and its weights untouched, so they can be dropped into any AF3-style sampler without retraining. Applied to two independently developed models, Boltz-2 and OpenFold-3, across five benchmarks (CASP15, CASP16, the PoseBusters monomer and complex sets, and the Boltz physical-validity test set), our method recovers perfect physical validity while preserving structural-accuracy and ligand-placement metrics. These gains are achieved with negligible runtime and memory overhead, providing a practical, model-agnostic route to physically valid all-atom structure prediction.
Abstract:AlphaFold 3-style cofolding models predict biomolecular complexes with high structural accuracy, yet a large fraction of their outputs are physically invalid: chains overlap at interfaces, ligand bond lengths and angles are distorted, rings are non-planar, and stereocentres are inverted. Current approaches either steer the sampler with physics-informed potentials, which multiplies sampling cost and memory overhead making inference impossible on large complexes, or finetune the model, costing time and tying the fix to one architecture. We observe that, unlike structural accuracy, physical validity is fully verifiable at inference time from quantities the sampler already holds. We therefore treat physical validity as a constrained inference problem and introduce two closed-form projection operators applied to the diffusion model's denoised clean-coordinate estimate, $\hat{x}_0$: an inter-chain van der Waals projection that pushes apart the most severely clashing atom pairs, and a ligand distance-geometry projection that restores bond lengths, angles, internal contacts, planarity and chirality. Both operators are local, sparse and displacement-capped, require no network evaluations, gradients or importance sampling, and leave the denoiser and its weights untouched, so they can be dropped into any AF3-style sampler without retraining. Applied to two independently developed models, Boltz-2 and OpenFold-3, across five benchmarks (CASP15, CASP16, the PoseBusters monomer and complex sets, and the Boltz physical-validity test set), our method recovers perfect physical validity while preserving structural-accuracy and ligand-placement metrics. These gains are achieved with negligible runtime and memory overhead, providing a practical, model-agnostic route to physically valid all-atom structure prediction.
Artificial Intelligence (cs.AI); Machine Learning (cs.LG)
arXiv:2610.07037 [cs.AI]
(or arXiv:2610.07037v1 [cs.AI] for this version)
https://doi.org/10.48550/arXiv.2610.07037 Focus to learn more arXiv-issued DOI via DataCite (pending registration)
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Full text under the publisher's open licence · 339 words
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