Biology subjects

Kravikass, M.

Publications and source records attributed to Kravikass, M..

4 recordsLinked to original sources

bioRxiv2026

Not All Charges Are Equal: Side-Chain Chemistry Reshapes the Disordered Ensemble of α-synuclein

The conformational ensembles of intrinsically disordered proteins (IDPs) are governed by the balance of electrostatic and hydrophobic interactions encoded in their primary sequences. Current polymer-physics models of IDPs frequently group amino acids by coarse-grained properties, such as net charge, often overlooking the distinct residues side-chain chemistries. Analysis across the IDP database reveals that these sequences are sensitive to specific residue identities, where the substitution of aromatic, proline, or hydrophobic groups serves as a primary driver of chain dimensions. However, these data also highlight that even subtle chemical variations between similarly charged residues can consistently shift global compaction. Here, we explore the role of residue identity using small angle X-ray scattering (SAXS) of seven -synuclein variants with progressively increasing numbers of lysine-to-arginine substitutions, two positively charged amino acids with different side-chain chemistry. We show that increasing arginine content drives a systematic compaction of the conformational ensemble, although variants with identical number of substitutions but different positional arrangements suggest influence to the sequence context. Moreover, while increasing salt concentrations shift the structural ensemble from a Gaussian toward a self-avoiding-walk statistics, the arginine-dependent contraction trend remains robust across both regimes. Molecular-dynamics simulations combined with SAXS data reveal that arginine substitutions reduce ensemble heterogeneity by stabilizing transient long-range contacts. Finally, aggregation assays demonstrate that this arginine-driven compaction correlates with an accelerated transition to amyloid fibrils. Our findings demonstrate that chemically subtle substitutions between similarly charged residues can fundamentally reshape the conformational ensemble of IDPs, suggesting that side-chain identity is a critical, yet underappreciated, determinant of protein disorder and proteotoxicity. O_TEXTBOXSignificance StatementIntrinsically disordered proteins (IDPs) are critical to cellular signaling and neurodegeneration, yet our ability to predict their behavior remains limited by a "coarse-grained" understanding of their sequences. We expand the view that net charge and patterning is a primary determinant of IDP dimensions by showing that lysine and arginine, residues identical in charge, exert opposite effects on the conformational landscape of -synuclein model-system. We find that arginine substitutions act as a "molecular glue", driving protein compaction and reducing ensemble heterogeneity. Crucially, this compaction accelerates amyloid aggregation, overturning the conventional assumption that collapsed states protect against fibrillization. This work demonstrates that side-chain identity and patterning are vital for protein homeostasis, providing a new framework for the rational design of IDP-based therapeutics. C_TEXTBOX

biophysics↗

bioRxiv2026

In silico model of neuronal pathfinding during spinal cord regeneration in zebrafish larvae

Functional spinal cord repair in zebrafish is governed by regeneration-favorable biochemical and mechanical cues within the lesion microenvironment. Alterations in extracellular matrix composition and stiffness are closely associated with axon regeneration. However, experimentally dissecting the interplay between mechanical signals and axonal regrowth in vivo remains technically challenging. Here, we present an agent-based modeling framework to simulate stiffness-mediated axonal growth trajectories across the lesion. We use this model to explore potential mechanisms underlying the characteristic growth patterns observed during zebrafish spinal cord regeneration. Computational predictions were qualitatively compared with confocal imaging data obtained from larval zebrafish. These phenomenological comparisons revealed a close agreement between simulated and experimentally observed axon growth, indicating that experimentally observed patterns could be governed by transient changes in the stiffness profile of the spinal cord and lesion microenvironment. Hence, our computational framework provides an in silico platform for investigating the role of mechanical cues in axon regeneration in the injured spinal cord.

biophysics↗

bioRxiv2026

In silico neuritogenesis model underpins mechanical interactionswith extracellular matrix as determinants of persistent axonal growthin stiffer microenvironments

It has been broadly recognized that the crosstalk between cells and their extracellular matrix (ECM) is crucial for the proper function of biological tissues. Relatively recently the role of ECM came in focus in the context of neuronal development and regeneration, where the effects of the ECM mechanics on the migration of neurons and neurite growth are still incompletely understood. Here we present an in silico twin framework for neurite growth focusing on its biophysical interactions with the ECM. This coarsegrained model accounts for viscoelastic liquid- and solid-like ECMs and neurite growth by ECM-mediated traction forces. Resulting growth trajectories can be rationalized based on the theory of random walks and polymer physics. To critically assess models predictive power, we performed experiments on neurites of hippocampal rat neurons growing in 3D collagen gels and observed a more persistent axon outgrowth in denser matricies. The model fully recapitulated the effect, thereby underpinning the central role of mechanical interactions with ECM as guiding principle of axonal growth. We argue that a combination our model with optical microscopy may provide an is silico twin helping to disentangle the contributions of "passive" physics from more complex effects of chemical queues or an apparent mechanosensing.

neuroscience↗

bioRxiv2025

Aberrant formation of long-range projections across different neurodevelopmental disorders converges on molecular and cellular nexuses

Establishing long-range connections during human brain development is an intricate multi-step process disturbed in many neurodevelopmental disorders (NDDs). The aberrant formation of these connections is caused by mutations in a plethora of different genes with distinct molecular functions, triggering the question of whether there are common key downstream mediators at which different pathologies are converging. We employed brain organoids to model early human brain developmental aspects of Coffin-Siris-like 9, Opitz BBB/G, and Pitt-Hopkins syndromes. These NDDs are caused by mutations in SOX11, MID1, and TCF4 respectively, and are characterized by a multitude of distinct symptoms yet share alterations in long-range projections as a common feature. Here, we uncover that mutations in all three genes phenotypically converge, showing impaired neurite extension with increased tortuosity and decreased growth speed resulting in shorter beelines. Moreover, the mutant neurites exhibit a decrease in growth persistence providing a conceptual framework explaining why long- but not short-range connections are affected. Correlating with the converging cellular phenotype, molecular characterization revealed a striking convergence on signaling pathways implicated in the interaction of neurites with their extracellular environment. In-silico modeling and perturbation of neurite outgrowth suggest that altered neurite-extracellular environment interactions are sufficient to recapitulate the mutant phenotypes but also facilitate the prediction of specific parameters causing disturbed neurite growth in mutant neurons.

developmental biology↗