IonNTxPred

IonNTxPred is a specialized web server designed for the prediction, design and scanning of peptides and proteins that impair ion channel function. It uses advanced Large Language Model (LLM), BLAST and Motif-based approaches. IonNTxPred has been trained on a comprehensive dataset of experimentally validated ion channel-targeting proteins and peptides.

Users can easily utilize the Prediction module by entering sequences directly into a text box or uploading a FASTA file. Upon submission, the server predicts whether the given sequence is likely to impair ion channels.

Besides prediction, IonNTxPred offers additional modules like Design (to generate and evaluate mutants), Protein Scanning (to scan longer protein sequences for toxic regions), BLAST (similarity based prediction), and Motif Scan (to map known motifs associated with ion channel impairment).

Furthermore, the server provides useful resources such as:

Download - to access the standalone version and datasets
Algorithm - to understand the underlying methodologies
Help - for user guidance and FAQs
Team - to learn about the development team
Contact - to reach us for queries or feedback

For general protein toxicity prediction (not specific to ion channels), users are encouraged to use our earlier server, ToxinPred3 or ToxinPred2.

Cite us: Rathore AS, Jain S, Mehta NK, Raghava GPS (2025) IonNTxPred: LLM-based Prediction and Designing of Ion Channel Impairing Proteins. Coming soon

IonNTxPred — Why ion channels matters?

Key points describing the biological importance of ion channels and the role of IonNTxPred.

Gatekeepers of electrical signaling: Ion channels precisely control the flow of Na⁺, K⁺, and Ca²⁺ across cell membranes, enabling nerve impulses, muscle contraction, and heartbeat regulation.
Fundamental to physiology: This regulated ion movement underpins critical processes — from synaptic transmission and cognition to cardiac rhythm and muscular activity.
Cause of disease when dysfunctional: Mutations or dysregulation of ion channels lead to channelopathies, including epilepsy, cardiac arrhythmias, and cystic fibrosis.
High-value therapeutic targets: Because they control cellular excitability, ion channels are prime targets for drugs and biologics in many therapeutic areas.
Primary targets of natural toxins: Venom-derived peptide toxins evolved to bind and modulate ion channels with high potency and selectivity — sometimes targeting multiple channel classes (moonlighting activity).
Challenge and opportunity for prediction: The diversity and occasional promiscuity of toxin–channel interactions make computational prediction difficult but highly valuable for safety assessment, discovery, and design.

IonNTxPred applies machine learning and protein-language models to identify peptide toxins targeting ion channels, aiding toxin biology, safety screening, and therapeutic discovery.

How do ion channel toxins work?

Figure: Mechanism of Ion Channel Impairment. Default functional ion channels (left) allow the regulated movement of Na⁺, K⁺, and Ca²⁺ ions. Peptides impair these channels (right) by blocking the pore, modifying gating, or altering channel structure, leading to disrupted ion flow.

Mechanism of Ion Channel Impairment by Peptides

Ion channels are critical for controlling ion movement across cell membranes, maintaining cellular communication and electrical signaling. Peptides that impair ion channels can:

1. Pore Blockers (Physical Occlusion)
- Mechanism: The toxin physically plugs the channel pore → ions cannot pass.
- Examples:
  - ω-Conotoxins (from Conus magus): block N-type Ca²⁺ channels by binding to the pore-forming region.
  - Charybdotoxin (from scorpions): blocks K⁺ channels by sitting in the pore.
2. Gating Modifiers (Voltage-Sensor Binding)
- Mechanism: The toxin binds to voltage-sensing domains, altering when the channel opens or closes. This can trap channels in an open state or prevent them from opening.
- Examples:
  - δ-Atracotoxin (funnel-web spider): slows inactivation of Na⁺ channels, keeping them open longer and causing excessive firing.
  - Hanatoxin (tarantula): shifts voltage dependence to inhibit Kv2.1 potassium channels.
3. Allosteric Modulators
- Mechanism: Toxins bind away from the pore but change channel conformation, making it easier or harder to open.
- Example:
  - Sea anemone toxins (e.g., ATX-II): bind Na⁺ channels → slow inactivation → prolonged depolarization.
4. Ligand-Competitive Blockers
- Mechanism: Some toxins mimic or compete with neurotransmitters for ligand-gated ion channels (e.g., nAChR).
- Example:
  - α-Bungarotoxin (from Bungarus multicinctus): binds nicotinic acetylcholine receptors, preventing ACh from binding → paralysis.
5. Membrane/Channel Environment Modifiers
- Mechanism: Some peptides affect the lipid–protein interface, changing how channels sense voltage or interact with the membrane.
- Example:
  - Certain spider toxins partition into membranes and modulate voltage sensor movement.

These interactions impair ion flow, leading to various physiological effects such as muscle paralysis, pain, or cardiac dysfunction depending on the target channel and organism.

Figure: Workflow of IonNTxPred. The pipeline involves systematic dataset preparation from experimentally validated ion channel-targeting peptides, followed by feature extraction to represent sequences numerically. Advanced machine learning models are then trained and evaluated to classify peptides, leading to the development of a user-friendly prediction tool for identifying potential ion channel-targeting peptides.

IonNTxPred - A webserver to predict ion channel impairing proteins

Welcome to IonNTxPred

IonNTxPred — Why ion channels matters?

How do ion channel toxins work?

Mechanism of Ion Channel Impairment by Peptides