https://github.com/animesh/foldseek

Foldseek enables fast and sensitive comparisons of large structure sets.

https://github.com/animesh/foldseek

Repository

Foldseek enables fast and sensitive comparisons of large structure sets.

https://github.com/animesh/foldseek/blob/master/

# Foldseek 
Foldseek enables fast and sensitive comparisons of large structure sets.



## Publications

[van Kempen M, Kim S, Tumescheit C, Mirdita M, Sding J, and Steinegger M. Foldseek:  fast and accurate protein structure search. bioRxiv, doi:10.1101/2022.02.07.479398  (2022)](https://www.biorxiv.org/content/10.1101/2022.02.07.479398)

## Webserver 
Search your protein structures against the [AlphaFoldDB](https://alphafold.ebi.ac.uk/) and [PDB](https://www.rcsb.org/) in seconds using our Foldseek webserver: [search.foldseek.com](https://search.foldseek.com) 

## Installation

    # static Linux AVX2 build (check using: cat /proc/cpuinfo | grep avx2)
    wget https://mmseqs.com/foldseek/foldseek-linux-avx2.tar.gz; tar xvzf foldseek-linux-avx2.tar.gz; export PATH=$(pwd)/foldseek/bin/:$PATH
    # static Linux SSE4.1 build (check using: cat /proc/cpuinfo | grep sse4_1)
    wget https://mmseqs.com/foldseek/foldseek-linux-sse41.tar.gz; tar xvzf foldseek-linux-sse41.tar.gz; export PATH=$(pwd)/foldseek/bin/:$PATH
    # static macOS build (universal binary with SSE4.1/AVX2/M1 NEON)
    wget https://mmseqs.com/foldseek/foldseek-osx-universal.tar.gz; tar xvzf foldseek-osx-universal.tar.gz; export PATH=$(pwd)/foldseek/bin/:$PATH
    # conda installer 
    conda install -c conda-forge -c bioconda foldseek

Other precompiled binaries for ARM64, PPC64LE amd SSE2 are available at [https://mmseqs.com/foldseek](https://mmseqs.com/foldseek).

### Quick start
`easy-search` can search single or multiple query structures formatted in PDB/mmCIF format (flat or `.gz`) against a target database (`example/`) of protein structures. It outputs a tab-separated file of the alignments (`.m8`) the fields are `query,target,fident,alnlen,mismatch,gapopen,qstart,qend,tstart,tend,evalue,bits`.

    foldseek easy-search example/d1asha_ example/ aln.m8 tmpFolder
    
The output can be customized with the `--format-output` option e.g. `--format-output "query,target,qaln,taln"` returns the query and target accession and the pairwise alignments in tab separated format. You can choose many different output columns.

```
query       Query sequence identifier 
target      Target sequence identifier
evalue      E-value
gapopen     Number of gap open events (note: this is NOT the number of gap characters)
pident      Percentage of identical matches
fident      Fraction of identical matches
nident      Number of identical matches
qstart      1-indexed alignment start position in query sequence
qend        1-indexed alignment end position in query sequence
qlen        Query sequence length
tstart      1-indexed alignment start position in target sequence
tend        1-indexed alignment end position in target sequence
tlen        Target sequence length
alnlen      Alignment length (number of aligned columns)
raw         Raw alignment score
bits        Bit score
cigar       Alignment as string. Each position contains either M (match), D (deletion, gap in query), or I (Insertion, gap in target)
qseq        Query sequence 
tseq        Target sequence
qaln        Aligned query sequence with gaps
taln        Aligned target sequence with gaps
qheader     Header of Query sequence
theader     Header of Target sequence
mismatch    Number of mismatches
qcov        Fraction of query sequence covered by alignment
tcov        Fraction of target sequence covered by alignment
empty       Dash column '-'
taxid       Taxonomical identifier (needs mmseqs tax db)
taxname     Taxon Name (needs mmseqs tax db)
taxlineage  Taxonomical lineage (needs mmseqs tax db)
qset        Query filename of FASTA/Q (useful if multiple files were passed to createdb)
qsetid      Numeric identifier for query filename
tset        Target filename of FASTA/Q (useful if multiple files were passed to createdb)
tsetid      Numeric identifier for target filename
qca         Calpha corrdinates of the query
tca         Calpha corrdinates of the target
alntmscore  TM-score of the alignment 
u           Rotation matrix (computed to by TM-score)
t           Translation vector (computed to by TM-score)
```

The target database can be pre-processed by `createdb`. This make sense if searched multiple times. 
 
    foldseek createdb example/ targetDB
    foldseek easy-search example/d1asha_ targetDB aln.m8 tmpFolder

### Important search parameters
    # sensitivity and speed
    -s                       adjust the sensitivity to speed trade-off.
                             lower is faster, higher more sensitive (fast: 7.5, highest sensitivity (default): 9.5)
    --max-seqs               adjust the amount of prefilter that are handed to the alignment. 
                             Increasing it can lead to more hits (default: 1000)
    -e                       List matches below this E-value (range 0.0-inf, default: 0.001)
                             Increasing it helps to report more distantly related structures.
                             Structures with an E-value of up to 1 might be still related.
    # other                         
    --alignment-type         0: 3Di Gotoh-Smith-Waterman (local, not recommended), 
                             1: TMalign (global, slow), 
                             2: 3Di+AA Gotoh-Smith-Waterman (local, default)
    -c                       list matches above this fraction of aligned (covered) residues (see --cov-mode) (default: 0.0) 
                             The higher the alignment coverage the more global is the alignment.
    --cov-mode               0: coverage of query and target, 1: coverage of target, 2: coverage of query

### Databases 
The `databases` command downloads pre-generated databases like PDB or AlphaFoldDB.
    
    # pdb  
    foldseek databases PDB100 pdb tmp 
    # alphafold db
    foldseek databases Alphafold/Proteome afdb tmp 

We currently support the following databases: 
```
  Name                   	Type     	Taxonomy	Url
- Alphafold/UniProt      	Aminoacid	     yes	https://alphafold.ebi.ac.uk/
- Alphafold/UniProt-NO-CA	Aminoacid	     yes	https://alphafold.ebi.ac.uk/
- Alphafold/UniProt50    	Aminoacid	     yes	https://alphafold.ebi.ac.uk/
- Alphafold/Proteome     	Aminoacid	     yes	https://alphafold.ebi.ac.uk/
- Alphafold/Swiss-Prot   	Aminoacid	     yes	https://alphafold.ebi.ac.uk/
- PDB                    	Aminoacid	     yes	https://www.rcsb.org
```

### Main Modules
- `easy-search`       fast protein structure search  
- `createdb`          create a database from protein structures (PDB,mmCIF, mmJSON)
- `databases`         download pre-assembled databases

### Using TMalign for the alignment
Foldseek supports to realign hits using TMalign as well as rescoring alignments using TMscore. 
```
foldseek easy-search example/d1asha_ example/ aln tmp --alignment-type 1
```
In case of the alignment type (`--alignment-type 1`) tmalign we sort the results by the TMscore normalized by query length. We write the TMscore into the e-value(=TMscore) as well as into the score(=TMscore*100) field.


### Rescore aligments using TMscore
Easiest way to get the alignment TMscore normalized by min(alnLen,qLen,targetLen) as well as a rotation matrix is through the following command:
```
foldseek easy-search example/ example/ aln tmp --format-output query,target,alntmscore,u,t
```

Alternative, it is possible to compute TMscores for the kind of alignment output (e.g. 3Di/AA) using the following commands: 
```
foldseek createdb example/ targetDB
foldseek createdb example/ queryDB
foldseek search queryDB targetDB aln tmpFolder -a
foldseek aln2tmscore queryDB targetDB aln aln_tmscore
foldseek createtsv queryDB targetDB aln_tmscore aln_tmscore.tsv
```

Output format `aln_tmscore.tsv`: query and target identifier, TMscore, translation(3) and rotation vector=(3x3)


### Search result visualisations
Foldseek can locally generate a search result HTML similiar to the [webserver](https://search.foldseek.com) by specifying the format mode `--format-mode 3`

```
foldseek easy-search example/d1asha_ example/ result.html tmp --format-mode 3
```



### Cluster structures 
The following command aligns the input structures all-against-all and keeps only alignments with 80% of the sequence covered by the alignment (-c 0.8) (read more about alignment coverage [here](https://github.com/soedinglab/MMseqs2/wiki#how-to-set-the-right-alignment-coverage-to-cluster)). It then clusters the results using greedy set cover algorithm. The clustering mode can be adjusted using --cluster-mode, read more [here](https://github.com/soedinglab/MMseqs2/wiki#clustering-modes). The clustering output format is described [here](https://github.com/soedinglab/MMseqs2/wiki#cluster-tsv-format).

```
foldseek createdb example/ db
foldseek search db db aln tmpFolder -c 0.8 
foldseek clust db aln clu
foldseek createtsv db db clu clu.tsv
```

### Query centered multiple sequence alignment 
Foldseek can generate a3m based multiple sequence alignments using the following commands. 
a3m can be converted to fasta format using [reformat.pl](https://raw.githubusercontent.com/soedinglab/hh-suite/master/scripts/reformat.pl) (`reformat.pl in.a3m out.fas`).
```
foldseek createdb example/ targetDB
foldseek createdb example/ queryDB
foldseek search queryDB targetDB aln tmpFolder -a
foldseek result2msa queryDB targetDB aln msa --msa-format-mode 6
foldseek unpackdb msa msa_output --unpack-suffix a3m --unpack-name-mode 0
```

### Compile from source
Compiling `foldseek` from source has the advantage of system-specific optimizations, which should improve its performance. To compile it `git`, `g++` (4.9 or higher) and `cmake` (3.0 or higher) are required. Afterwards, the foldseek binary will be located in the `build/bin` directory.

    git clone https://github.com/steineggerlab/foldseek.git
    cd foldseek
    mkdir build
    cd build
    cmake -DCMAKE_BUILD_TYPE=RELEASE -DCMAKE_INSTALL_PREFIX=. ..
    make -j
    make install
    export PATH=$(pwd)/foldseek/bin/:$PATH

:exclamation: If you want to compile `foldseek` on macOS, please install and use `gcc` from Homebrew. The default macOS `clang` compiler does not support OpenMP (by default) and `foldseek` will not be able to run multi-threaded. Adjust the `cmake` call above to:

    CC="$(brew --prefix)/bin/gcc-11" CXX="$(brew --prefix)/bin/g++-11" cmake -DCMAKE_BUILD_TYPE=RELEASE -DCMAKE_INSTALL_PREFIX=. ..

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