Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.64898/2026.08.16.745091

Morpheus-3D: Structural Diversity-Guided Detection and Localization of Protein Fold Switching

Kuniyil, S.·Subramanian, V.·Arun, A.·Lakshmanan, A.·Sekhar, A.·Srivastava, A.
View original source ↗Export metadata ↓

Abstract

Proteins that reversibly adopt multiple stable folds challenge the classical sequence-structure paradigm, yet their discovery remains limited because fold switching is difficult to detect experimentally and current computational methods fail to resolve the underlying conformationally plastic regions. Here we present Morpheus-3D, a sequence-based framework that quantifies residue-level tertiary structural diversity using entropy profiles derived from the Foldseek 3Di structural alphabet. By capturing variation in tertiary interaction environments rather than secondary structure alone, Morpheus-3D identifies fold-switching proteins while simultaneously localizing the sequence regions responsible for structural transitions. The framework outperforms existing predictors, accurately recovers experimentally characterized switching regions, generalizes to recently discovered natural and engineered fold-switching proteins absent from training, and detects conformational plasticity inaccessible to secondary-structure-based approaches. Application to 57 representative proteomes reveals that fold-switching potential is widespread but enriched in regulatory, pathogenic, and environmentally adaptive lineages. Integration with ancestral sequence reconstruction further un-covers evolutionary trajectories through which conformational plasticity emerges. To make these predictions directly accessible, we implemented Morpheus-3D as an interactive web platform (https://morpheus.slicearrow.com/), in which per-residue entropy profiles, sequence and three-dimensional structure are displayed together and respond as one, allowing predicted fold-switching regions to be mapped onto the structure and exported for downstream analysis. Morpheus-3D provides a scalable framework for discovering metamorphic proteins and investigating the origins, mechanisms, and evolution of structural plasticity directly from sequence.

Explore related subjects

biophysicsPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Kuniyil, S., Subramanian, V., Arun, A., Lakshmanan, A., Sekhar, A., Srivastava, A.. 2026-08-21. Morpheus-3D: Structural Diversity-Guided Detection and Localization of Protein Fold Switching. https://doi.org/10.64898/2026.08.16.745091

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Diatom Logic: Rewritable active nematic circuits in tidal-flat ecosystems

At the ocean-land interface lies a critical yet largely ignored ecosystem of tidal flats[1]. These habitats are colonized by diatoms that form thin surface biofilms, creating ecosystem-scale cellular collectives stretching meters to kilometers[2-4]. How these collectives coordinate functions across vast spatiotemporal scales remains poorly understood. This task requires both long-distance transfer and long-term storage of information[5, 6]. In cellular collectives, trigger waves have been known to provide rapid, non-attenuating signaling[7-9], while extracellular matrices allow cells to externalize structural memory[10-12]. Yet, how propagating signals and structural memory integrate to shape collective functions remains elusive. Combining field observations with laboratory reconstitution, we show that tidal-flat diatoms assemble active nematic circuits that physically wire trigger-wave routing into structural memory. Here, trigger waves recruit resting diatoms into polarized motion steered by the nematic director, and topological defects act as gates that focus or bifurcate propagating wave fronts. Memory follows a fast-read, slow-write rule: rapid signals deform the cellular nematic, while slowly evolving cell-deposited mucilage retains a hidden orientational template that guides alignment recovery. Strikingly, recurrent waves progressively remodel the nematic architecture, letting the collective reshape its future routing. Coupling rapid wave propagation to extracellular memory allows collectives to resolve the stability-plasticity dilemma, maintaining structural cohesion while adapting to recurrent stimuli. Our work reveals previously hidden adaptive nematic circuits that self-organize at ecological scales, establishing a physical framework for time-programmable active materials.

biophysics↗
bioRxiv2026

The CAHRA Challenge: A Community-Wide Assessment of Cryo-EM Heterogeneous Reconstruction Algorithms

The ability of cryo-electron microscopy (cryo-EM) to interrogate the atomic structure and motion of biomolecules has motivated the development of a wide range of algorithms for heterogeneity analysis. However, evaluating and comparing these methods remains challenging because ground-truth structures are generally unknown for experimental samples. Here, we introduce the 2026 Community-Wide Assessment of Heterogeneous Reconstruction Algorithms (CAHRA), a community-wide challenge centered on three benchmark datasets that probe distinct tasks in heterogeneity analysis. These include (1) compositional heterogeneity arising from mixtures of distinct protein complexes, (2) continuous conformational variability and atomic modeling, and (3) entanglement between molecular conformation and particle pose. We describe the design, construction, and validation of these datasets, as well as their use in the recently completed CAHRA Challenge.

biophysics↗
bioRxiv2026

Microscope control with a natural language agent

Microscopy underpins modern biology, but acquiring high-quality data from complex experiments at scale remains challenging. Smart microscopy can standardize and automate data collection, but each experiment-specific solution requires coding expertise and development time. To address this, we present MicroClaw, an AI agent that advises on experiment- and system-specific parameters and approaches and collaboratively plans and executes diverse, complex, and reusable imaging workflows across microscope platforms, without requiring expert knowledge.

biophysics↗