← 研踪 PaperTrailarXiv:2611.04287 · v2
Predicting protein structures at any folding stage from sequence
首次提交 2026-11-03 12:15
版本更新 2026-11-04 11:46
雷达观测 2026-11-05 10:08
摘要
Protein structure prediction has largely focused on native conformations, leaving the continuum of unfolded states, folding intermediates, and native structures difficult to access. We present FoldScape, a sequence-conditioned deep learning framework for generating protein conformational ensembles at specified folding fractions $Q$. Trained on approximately one million conformations from 10,000 protein sequences, FoldScape combines coarse-grained folding and all-atom mechanical-unfolding trajectories. It reconstructs three-dimensional $C_α$ chains through hierarchical sliding-window regressions of inter-residue distances, chain-level assembly, and a rectified-flow decoder. By conditioning on folding progress, FoldScape generates conformations from unfolded states through intermediates to native-state structures without protein-specific molecular dynamics at inference. In matched-sample comparisons, FoldScape achieves median conformational-space coverage of 0.989, 0.722, and 0.877 along radius of gyration, fraction of native contacts $Q$, and secondary-structure fraction, respectively, versus 0.05, 0.05, and 0.10 for seed-varied AlphaFold 3 ensembles. Coverage advantages are consistent across the evaluated proteins and robust to binning choices. Reconstruction accuracy remains approximately stable across the evaluated stages of a folding trajectory, and stride-one crop-and-superpose inference extends predictions to chains several times longer than the single-pass limit. Analyses of mechanical-unfolding trajectories show residue-resolved pathways, reproducible extension-conditioned observables across pulling velocities, and geometrically coherent segments in partially unfolded chains. FoldScape extends sequence-based structure prediction beyond a single folded endpoint to controllable conformational-ensemble generation across protein folding.
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v2 · 2026-11-04 11:46 · 最新观测版本
Predicting protein structures at any folding stage from sequence
Protein structure prediction has largely focused on native conformations, leaving the continuum of unfolded states, folding intermediates, and native structures difficult to access. We present FoldScape, a sequence-conditioned deep learning framework for generating protein conformational ensembles at specified folding fractions $Q$. Trained on approximately one million conformations from 10,000 protein sequences, FoldScape combines coarse-grained folding and all-atom mechanical-unfolding trajectories. It reconstructs three-dimensional $C_α$ chains through hierarchical sliding-window regressions of inter-residue distances, chain-level assembly, and a rectified-flow decoder. By conditioning on folding progress, FoldScape generates conformations from unfolded states through intermediates to native-state structures without protein-specific molecular dynamics at inference. In matched-sample comparisons, FoldScape achieves median conformational-space coverage of 0.989, 0.722, and 0.877 along radius of gyration, fraction of native contacts $Q$, and secondary-structure fraction, respectively, versus 0.05, 0.05, and 0.10 for seed-varied AlphaFold 3 ensembles. Coverage advantages are consistent across the evaluated proteins and robust to binning choices. Reconstruction accuracy remains approximately stable across the evaluated stages of a folding trajectory, and stride-one crop-and-superpose inference extends predictions to chains several times longer than the single-pass limit. Analyses of mechanical-unfolding trajectories show residue-resolved pathways, reproducible extension-conditioned observables across pulling velocities, and geometrically coherent segments in partially unfolded chains. FoldScape extends sequence-based structure prediction beyond a single folded endpoint to controllable conformational-ensemble generation across protein folding.
查看此版本解读 →查看此版本原文 ↗v1 · 2026-11-03 12:15
Predicting protein structures at any folding stage from sequence
Protein structure predictors reliably identify native conformations, but do not describe the continuum connecting unfolded ensembles to folded states. Here we present FoldScape, a sequence-conditioned deep learning framework that generates C$α$ conformational ensembles at a specified folding fraction $Q$. FoldScape reconstructs three-dimensional chains through hierarchical, sliding-window regressions of one-dimensional inter-residue distances, followed by chain assembly and sampling with a rectified-flow decoder. It is trained on multi-scale coarse-grained folding trajectories and all-atom mechanical-unfolding trajectories. Across 20 human proteins (36-857 residues), at matched sample size, FoldScape covers about an order of magnitude more of the folding coordinate than seed-varied AlphaFold 3 ensembles, robustly across proteins, order parameters and binning choices. AlphaFold 3 better anchors the immediate native vicinity, which FoldScape does not reach, making the approaches complementary. FoldScape reconstruction accuracy remains approximately constant along $Q$, from collapsed coil to near-native globule, rather than deteriorating away from the native state. A stride-one crop-and-superpose scheme extends inference to chains several times longer than a single chain-level forward pass. We also show that training trajectories resolve mechanical unfolding at residue resolution, that elongation-conditioned ensembles exhibit reproducible continuous observables across pulling velocities, and that partially unfolded chains form geometrically coherent segments. FoldScape thus combines broad coverage of folding stages with stable reconstruction accuracy, without per-protein simulation.
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