Biology subjects

Lakshmanan, A.

Publications and source records attributed to Lakshmanan, A..

3 recordsLinked to original sources

bioRxiv2026

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

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.

biophysics↗

bioRxiv2026

Rett syndrome lifespan extension in mice via AI-guided ADAR editing

Rett syndrome is a severe neurodevelopmental disorder primarily caused by mutations in the MECP2 gene. A significant subset of severe cases are driven by nonsense mutations that generate premature stop codons, leading to loss of functional MeCP2 protein. Here, we describe a novel therapeutic strategy that uses endogenous adenosine deaminase acting on RNA (ADAR) enzymes to correct the R168X mutation at the RNA level. Using generative artificial intelligence trained on large empirical datasets, we engineered guide RNAs (gRNAs) that recruit endogenous ADAR to convert the mutant stop codon (UGA) into a tryptophan (UGG) to restore full-length MeCP2. Once incorporated into an optimized expression system based on endogenous small nuclear RNA regulatory elements and packaged into adeno-associated virus, these gRNAs enabled precise RNA editing at the target site with minimal off-target activity across the transcriptome while restoring full-length MeCP2 protein expression in patient-derived induced pluripotent stem cell neurons. Delivered intravenously to an R168X mouse model, the gRNAs achieved ~70% targeted RNA editing and substantially restored MeCP2 throughout the brain resulting in markedly improved Rett-like phenotypes and significantly extended lifespan. These findings demonstrate that AI-guided ADAR-mediated RNA editing is a precise and efficient technology for correcting nonsense mutations, with therapeutic potential for Rett syndrome and other genetic diseases.

neuroscience↗

bioRxiv2023

Ultrasonic reporters of calcium for deep tissue imaging of cellular signals

Calcium imaging has enabled major biological discoveries. However, the scattering of light by tissue limits the use of standard fluorescent calcium indicators in living animals. To address this limitation, we introduce the first genetically encoded ultrasonic reporter of calcium (URoC). Based on a unique class of air-filled protein nanostructures called gas vesicles, we engineered URoC to produce elevated nonlinear ultrasound signal upon binding to calcium ions. With URoC expressed in mammalian cells, we demonstrate noninvasive ultrasound imaging of calcium signaling in vivo during drug-induced receptor activation. URoC brings the depth and resolution advantages of ultrasound to the in vivo imaging of dynamic cellular function and paves the way for acoustic biosensing of a broader variety of biological signals.

bioengineering↗