Folddisco

Folddisco is tool for searching discontinuous motifs in protein structures. It is designed to handle large-scale protein databases with efficiency, enabling the detection of structural motifs across thousands of proteomes or millions of structures.

Publications

Kim H, Kim RS, Mirdita M, Yoon J, Steinegger M. Structural motif search across the protein-universe with Folddisco. Nature Biotechnology, (2026)

Latest updates (PDF).

Webserver

Search protein structures motifs against the AlphaFoldDB and PDB in seconds using the Folddisco webserver (code): search.foldseek.com/folddisco 🚀

Installation

# Install from Bioconda
conda create -n folddisco -c conda-forge -c bioconda folddisco

# Install through docker
docker pull ghcr.io/steineggerlab/folddisco:master

# Precompiled binary for Linux x86-64
wget https://mmseqs.com/folddisco/folddisco-linux-x86_64.tar.gz; tar xvfz folddisco-linux-x86_64.tar.gz; export PATH=$(pwd)/folddisco/bin/:$PATH

# Precompiled binary for Linux ARM64
wget https://mmseqs.com/folddisco/folddisco-linux-arm64.tar.gz; tar xvfz folddisco-linux-arm64.tar.gz; export PATH=$(pwd)/folddisco/bin/:$PATH

# macOS (universal, works on Apple Silicon and Intel Macs)
wget https://mmseqs.com/folddisco/folddisco-macos-universal.tar.gz; tar xvfz folddisco-macos-universal.tar.gz; export PATH=$(pwd)/folddisco/bin/:$PATH

Compile from source

Compiling from source requires the Rust toolchain (Cargo). Installation instructions are available here.

git clone https://github.com/steineggerlab/folddisco.git
cd folddisco
cargo install --features foldcomp --path .

Quick start

Folddisco queries a database of precomputed geometric hashes computed from structures.

Download pre-build database

You can download the pre-built human proteome index and use it to search for a common motif, like a zinc finger.

This example is fully self-contained. You can copy and paste the entire block into your terminal.

# Download human proteome index. Use wget or aria2 to download the index.
cd index
aria2c https://opendata.mmseqs.org/folddisco/h_sapiens_folddisco.tar.lz4

# Extract the index
lz4 -dc h_sapiens_folddisco.tar.lz4 | tar -xvf -
cd ..

Pre-built Indices

Download pre-built index files:

Human proteome
E. coli proteome
AFDB proteome of 16 model organisms
Swiss-Prot
AFDB50
ESM30
PDB
To get the old version of Folddisco indices, please visit https://opendata.mmseqs.org/folddisco/
- *.tar.gz indices are legacy indices (version 1.0), which are not compatible with version 2.0 or later. Please use *.tar.lz4 indices; version 3.0 reads them unchanged.
- AFDB50 (afdb50_v4_folddisco* + afdb50_v4*)
- ESM30 (highquality_clust30_folddisco* + highquality_clust30*)

Build an custom index

The command below will read all PDB or mmCIF from serine_peptidases folder and generate an index serine_peptidases_folddisco.

folddisco index -p data/serine_peptidases -i index/serine_peptidases_folddisco

Querying a Single Motif

To search for a specific structural motif, you'll use three main flags:

-p: Provides the query protein's structure file (PDB/mmCIF).
-q: Specifies the comma-separated list of residues that form your motif.
-i: Points to the target database index you want to search against.

If you omit the -q flag, folddisco defaults to a "whole structure" search. It will find all possible motifs from your entire query protein and search for them in the index.

# Search for the catalytic triad from 4CHA.pdb against the indexed peptidases.
folddisco query -i index/serine_peptidases_folddisco -p query/4CHA.pdb -q B57,B102,C195

Residue & motif syntax

We allow to customize the query motif using some motif syntax.

Residues: B57 = chain B, residue number 57. Separation with _ is allowed (e.g., B_57, AA_250, 10_100). Ranges are inclusive: 1-10.
Lists: comma-separated: B57,B102,C195.
Substitutions: :<ALT> allows alternatives:
- Single amino acid: 164:H
- Set: 247:ND (Asp or Asn)
- Wildcard/categories:
  - X: any amino acid
  - p: positively charged (Arg, His, Lys)
  - n: negatively charged (Asp, Glu)
  - h: polar (Asn, Gln, Ser, Thr, Tyr)
  - b: hydrophobic (Ala, Cys, Gly, Ile, Leu, Met, Phe, Pro, Val)
  - a: aromatic (His, Phe, Trp, Tyr)
  - *: --aa-subst scheme (default blosum62)

Searching Multiple Motifs (Batch Mode)

To search for many motifs at once, you can provide a single query file to the -q flag (and omit the -p flag).

This file must be a tab-separated text file with these columns:

Column 1: Path to the query structure (PDB/mmCIF).
Column 2: Comma-separated list of motif residues.
Column 3: (Optional) path to the output file (default: stdout).

# Search a zinc finger motif against pre-downloaded human proteome (see Download pre-build database)
folddisco query -i index/h_sapiens_folddisco -q query/serine_peptidase.txt

Commands

Usage of Query Module

folddisco query -i <INDEX> -p <QUERY_PDB> [-q <QUERY_RESIDUES> -d <DISTANCE_THRESHOLD> -a <ANGLE_THRESHOLD> --skip-match -t <THREADS>]

Important parameter:

-d: Distance tolerance in Å, increase sensitivity during the prefilter (default: 0.5)
-a: Angle tolerance in degrees, increase sensitivity during the prefilter (default: 5)
--sensitive: Wider, slower search for sensitive matching
--confident: Keep only confident hits
--aa-subst: Substitute every query residue by scheme
--novelty-mode: One KNOWN/PARTIAL/NOVEL row per query instead of a hit list
--skip-match: Skips residue matching and RMSD calculation (prefilter only, much faster with same ranking)
--top: Only report top N hits from the prefilter (controls speed and size of result)
-t: Threads used for search
-v: Verbose output

Example Querying

# Search with default settings (sorted by IDF, then RMSD)
folddisco query -p query/4CHA.pdb -q B57,B102,C195 -i index/h_sapiens_folddisco -t 6
folddisco query -p query/1G2F.pdb -q F207,F212,F225,F229 -i index/h_sapiens_folddisco -d 0.5 -a 5 -t 6
folddisco query -p query/1LAP.pdb -q 250,255,273,332,334 -i index/h_sapiens_folddisco --skip-match -t 6 # Skip residue matching

# Query file given as separate text file
folddisco query -q query/zinc_finger.txt -i index/h_sapiens_folddisco -t 6 -d 0.5 -a 5

# Querying a whole structure
folddisco query -i index/h_sapiens_folddisco -p query/1G2F.pdb -t 6 --skip-match
# For a long query, low `--sampling-ratio` can be used to speed up the search
folddisco query -i index/h_sapiens_folddisco -p query/1G2F.pdb -t 6  --skip-match --sampling-ratio 0.3

# Using a query file with distance and angle thresholds
folddisco query -i index/h_sapiens_folddisco -q query/knottin.txt -d 0.5 -a 5 --skip-match -t 6

# Query with amino-acid substitutions and range. 
# Alternative amino acids can be given after colon. 
# X: substitute to any amino acid, p: positive-charged, n: negative-charged, h: hydrophilic, b: hydrophobic, a: aromatic
# Here's enolase query with 3 substitutions; Allow His at 164, Asp & Asn at 247, and His at 297. (Install e_coli_folddisco index first)
folddisco query -p query/2MNR.pdb -q 164:H,195,221,247:ND,297:H -i index/e_coli_folddisco -d 0.5 -a 5 --top 10 --header --per-structure
# Range can be given with dash. This will query first 10 residues and 11th residue with subsitution to any amino acid.
folddisco query -p query/4CHA.pdb -q 1-10,11:X -i index/h_sapiens_folddisco -t 6 --serial-index

# Advanced query with filtering and sorting
## Based on connected node and rmsd
folddisco query -q query/zinc_finger.txt -i index/h_sapiens_folddisco -t 6 --connected-node 0.75 --rmsd 1.0

## Coverage based filtering & top N filtering without residue matching
folddisco query -q query/zinc_finger.txt -i index/h_sapiens_folddisco -t 6 --covered-node 3 --top 1000 --per-structure --skip-match

# Print top 100 structures with sorting by score
folddisco query -p query/4CHA.pdb -q B57,B102,C195 -i index/h_sapiens_folddisco -t 6 --top 100 --per-structure --sort-by idf
folddisco query -q query/zinc_finger.txt -i index/h_sapiens_folddisco -t 6 --covered-node 4 --top 100 --sort-by idf --per-structure --skip-match

# Comprehensive filtering with multiple criteria
folddisco query -q query/zinc_finger.txt -i index/h_sapiens_folddisco -t 6 -d 0.5 -a 10.0 --ca-distance 1.0 --covered-node-ratio 0.3 --max-node-ratio 0.35 --rmsd 5.0 --tm-score 0.2 --gdt-ts 0.25 --gdt-ha 0.15 --chamfer 5.5 --hausdorff 12.0 --sort-by node_count,gdt_ts,rmsd,idf --format-output tid,node_count,gdt_ts,rmsd,idf,matching_residues,query_residues

Confident hits

By default a query returns every structure that matched any part of the motif, partial matches included. --confident keeps only the confident, full ones: at least 80% of the query residues matched within 1 Å RMSD.

Amino acid substitution

--aa-subst <MODE> lets every query residue without an explicit :ALT match similar residues; :* does the same for one residue.

mode	alternatives for the observed residue
`blosum62`	positive BLOSUM62 score (default for `:*`)
`group`	same class: RHK, DE, NQST, FWY, AVLIMC, GP
`size`	same IMGT side-chain volume class: GAS, CDPNT, QEHV, MILKR, FWY

folddisco query -p query/4CHA.pdb -q B57,B102:*,C195 -i index/h_sapiens_folddisco -t 6
folddisco query -p query/4CHA.pdb -q B57,B102,C195 -i index/h_sapiens_folddisco -t 6 --aa-subst group

Usage of Index Module

folddisco index -p <PDB_DIR|FOLDCOMP_DB> -i <INDEX_PATH> -t <THREADS> [-d <DISTANCE_BINS> -a <ANGLE_BINS> -y <HASH_TYPE>]

Important parameter:

-d: Number of distance bins (default for default type: 16)
-a: Number of angle bins (default for default type: 4)
-y, --type: Hash type: default, pdb, trrosetta, ppf, 3di
-t: Threads
-v: Verbose output

Examples

# Default indexing; a directory or a Foldcomp database
folddisco index -p h_sapiens -i index/h_sapiens_folddisco -t 12

# Custom hash type and bins
folddisco index -p h_sapiens -i index/h_sapiens_pdbtype -t 12 -y pdb -d 8 -a 3

Index-time expansion

For small databases, the query expansion can be stored in the index instead (default: off).

folddisco index -p data/serine_peptidases -i index/serine_expanded -t 12 --expand-radius 1 --aa-subst blosum62
folddisco query -p query/4CHA.pdb -q B57,B102,C195 -i index/serine_expanded

--expand-radius, --expand-distance (0.5 Å) and --expand-angle (5°) mirror the query options.

Output

Match Result

Default output which prints out one matching motif per line

tid	node_count	idf	rmsd	matching_residues	query_residues
data/serine_peptidases/4cha.pdb	3	8.7616	0.0000	B57,B102,C195	B57,B102,C195
data/serine_peptidases/4cha.pdb	3	8.7616	0.0874	F57,F102,G195	B57,B102,C195
data/serine_peptidases/1pq5.pdb	3	4.1178	0.2609	A56,A99,A195	B57,B102,C195
data/serine_peptidases/1ju3.pdb	2	1.4739	0.7792	_,A223,A234	B57,B102,C195
data/serine_peptidases/1l7a.pdb	2	1.4739	0.7883	_,A146,A127	B57,B102,C195
data/serine_peptidases/1l7a.pdb	2	1.4739	0.8078	_,B146,B127	B57,B102,C195
data/serine_peptidases/1azw.pdb	2	4.6439	0.9234	A179,_,B176	B57,B102,C195

tid: Identifier of the target protein structure
node_count: Number of nodes in the match
idf: Inverse document frequency score of matched structure
rmsd: Root mean square deviation
matching_residues: Residue indices in the match (comma-separated, _ for no match)
query_residues: Residue indices in the query (comma-separated)

Residues are written as chain + residue number (B57). When a multi-character AA or a numeric 10 chain ID is used, the field switches to AA_250 / 10_250 instead. Pass --chain-sep to get the separated form for every structure.

Structure Result

Output with one structure per line (--per-structure)

tid	idf	total_match_count	node_count	edge_count	max_node_cov	min_rmsd	nres	plddt	matching_residues	db_key	query_residues
data/serine_peptidases/4cha.pdb	0.6138	8	3	6	3	0.0000	477	13.5404	B57,B102,C195:0.0000;F57,F102,G195:0.0874	4	B57,B102,C195
data/serine_peptidases/1pq5.pdb	0.4869	4	3	4	3	0.2609	224	5.1340	A56,A99,A195:0.2609	3	B57,B102,C195
data/serine_peptidases/1ju3.pdb	0.0617	2	2	2	2	0.7792	570	19.4881	_,A223,A234:0.7792	1	B57,B102,C195
data/serine_peptidases/1l7a.pdb	0.0584	2	2	2	2	0.7883	636	11.7037	_,A146,A127:0.7883;_,B146,B127:0.8078	2	B57,B102,C195
data/serine_peptidases/1azw.pdb	0.1856	2	2	2	2	0.9234	626	34.2399	A179,_,B176:0.9234	0	B57,B102,C195

tid: Identifier of the target protein structure
idf: Inverse document frequency score with length penalty; Higher score indicates more matches within smaller structures
total_match_count: Total number of matches
node_count: Number of nodes in the structure
edge_count: Number of edges in the structure
max_node_cov: Maximum node coverage
min_rmsd: Minimum root mean square deviation
nres: Number of residues
plddt: Predicted local distance difference test score
matching_residues: Residue indices in the match (comma-separated, _ for no match, semicolon-separated for multiple matches with RMSD)
key: Numeric identifier of the structure
query_residues: Residue indices in the query (comma-separated)

Display Options

--per-structure: Outputs results per structure.
--per-match: Outputs results per match.
--sort-by: Sorts results by given columns (comma-separated).
--format-output: Custom output format using column names.
--top <N>: Outputs top N results.
--header: Outputs header for the result.

Sorting Defaults

This is the default sorting order:

match_score:desc,rmsd:asc per match
structure_score:desc,min_rmsd:asc per structure
--sort-by idf:desc,rmsd:asc for compatibility with previous versions.

We are updating the score calculation for better ranking of matches. This is current definition of the scores:

match_score: idf × (matched fraction of the query)² × TM-score.
structure_score: matched residues² × √idf / (1 + RMSD).

Name		Name	Last commit message	Last commit date
.github		.github
data		data
docs		docs
examples		examples
index		index
lib		lib
query		query
scripts		scripts
src		src
tests		tests
.gitignore		.gitignore
CHANGELOG.md		CHANGELOG.md
Cargo.lock		Cargo.lock
Cargo.toml		Cargo.toml
Dockerfile		Dockerfile
LICENSE.md		LICENSE.md
README.md		README.md
build.rs		build.rs
quick_start.sh		quick_start.sh

Navigation Menu

Repository navigation

About

Repository files navigation

Folddisco

Publications

Webserver

Installation

Quick start

Download pre-build database

Pre-built Indices

Build an custom index

Querying a Single Motif

Residue & motif syntax

Searching Multiple Motifs (Batch Mode)

Commands

Usage of Query Module

Example Querying

Confident hits

Amino acid substitution

Usage of Index Module

Examples

Index-time expansion

Output

Match Result

Structure Result

Display Options

Sorting Defaults

Contributions

About

Releases

Packages

Used by

Contributors

Languages

Latest commit

History

Folders and files

Repository files navigation

Folddisco

Publications

Webserver

Installation

Quick start

Download pre-build database

Pre-built Indices

Build an custom index

Querying a Single Motif

Residue & motif syntax

Searching Multiple Motifs (Batch Mode)

Commands

Usage of Query Module

Example Querying

Confident hits

Amino acid substitution

Usage of Index Module

Examples

Index-time expansion

Output

Match Result

Structure Result

Display Options

Sorting Defaults

Contributions

About

Topics

Resources

Stars

Watchers

Forks

Releases

Packages

Used by

Contributors

Languages