| Category |
Name |
Description |
Features and limitations |
| ASR |
Bali-phy |
A standalone tool for the estimation of multiple sequence alignments and
evolutionary trees
|
Features: Excellent performance on tested protein data sets |
|
Limitations: Tends to systematically under-align on the biological
sequence data
|
| IQ-TREE |
Standalone software and web tool for the inference of phylogenetic trees
using the maximum-likelihood approach
|
Features: It is an integral component of many biomedical research
open-source applications such as Galaxy, Nextstrain, and QIIME 2
|
|
Limitations: Both IQ-Tree- and RaxML-NG-inferred maximum-likelihood gene
trees have been suggested to have reproducibility issues
|
| Molecular Evolutionary Genetics Analysis (MEGA X) |
User-friendly software for molecular evolution analysis and construction
of phylogenetic trees
|
Features: Easy-to-use graphical user interface (GUI) with good
documentation available; works across all platforms
|
|
Limitations: Works like a black box for some parameters, with no user
control
|
| MrBayes |
A program for Bayesian inference and model choice across a wide range of
phylogenetic and evolutionary models
|
Features: GPU acceleration available |
|
Limitations: Requires quite complex input data, which can hinder
non-experts from performing ASR successfully
|
| Phylogenetic Analysis by Maximum Likelihood (PAML) |
Standalone software and web tool to perform phylogenetic analysis using
the maximum likelihood approach
|
Features: Has a GUI version; very customizable |
| Limitations: Steep learning curve for novice users |
| Randomized Axelerated Maximum Likelihood (RAxML) |
A standalone tool for ASR using the maximum-likelihood approach; a GUI
is being developed
|
Features: Has a GUI (under development but already available for use)
|
|
Limitations: Both IQ-Tree- and RaxML-NG-inferred maximum-likelihood gene
trees have been suggested to have reproducibility issues
|
| The FastML Server (FastML) |
A web tool for ASR using the maximum-likelihood approach
|
Features: Easy-to-use web tool; can take unaligned sequences as input
|
| Limitations: Accepts only the FASTA file format as input |
| Allostery |
DFI |
A protocol developed to identify per-residue contributions to a
protein's overall dynamical profile
|
Features: Code easily available and ready to use |
| Limitations: Requires atomic coordinates |
| Ohm |
Web tool that predicts allosteric sites and inter-residue correlation
and identifies the allosteric pathways between them
|
Features: Easy-to-use web tool requiring only the insertion of a 3D
structure
|
|
Limitations: Structure-based predictions do not take dynamics into
account
|
| SPM |
Tool developed for the identification of distal mutations affecting
function, based on the shortest-path-map algorithm
|
Features: Uses long dynamic simulations to predict allosteric sites
|
| Limitations: Poor availability of the code |
| Databases (assorted) |
BRENDA |
Electronic repository containing molecular and biochemical information
on enzymes
|
Features: Several different queries are available as examples;
integrates CATH and SCOPe
|
| Limitations: Requires login and there is a 'professional' version |
| PDB |
A protein databank containing more than 179 000 macromolecular
structures
|
Features: General database for protein structures obtained through NMR,
X-ray crystallography, and cryoelectron microscopy
|
|
Limitations: Contains redundant data and the search function could be
better
|
| UniProt |
A central repository of protein data created by combining the
Swiss-Prot, TrEMBL, and PIR-PSD databases
|
Features: De facto go-to database for general protein
information
|
| Limitations: Overwhelming amount of data for newcomers |
| Databases (family information) |
CATH Protein Structure Classification database |
A database containing information about the evolutionary relationships
of protein domains
|
Features: Huge open-source database helps with automated implementation
in one's own workflows
|
| Limitations: Drug compound information is still being developed |
| Fuzzle |
A database containing evolutionary information about protein fragments
|
Features: Evolutionary information on fragments as opposed to full
proteins only
|
|
Limitations: Hierarchical databases can lead to misclassification when
slight differences are present in the sequences
|
| Pfam |
A database with information about protein families, represented by
multiple sequence alignments generated using Hidden Markov models
|
Features: Constant development and integration with other European
Bioinformatics Institute (EBI) tools
|
|
Limitations: There is a high-quality database and a low-quality database
that can lead to errors
|
| SCOP |
A database of proteins classified based on structural relatedness, such
as superfamilies, families, and folds
|
Features: Uses data deposited in the PDB to group proteins; curated to
be non-redundant
|
| Limitations: New version is not totally backwards compatible |
| Modeling |
AlphaFold |
Protein prediction tool using neural networks; achieved a score twice as
good as the second-best protein predictor in CASP14
|
Features: New gold standard for protein structure prediction; makes use
of a newly developed neural network
|
|
Limitations: It is better where others were good, but still lacks good
loop region predictions.
|
| iTasser |
Both a web tool and a standalone tool, it predicts protein structure
using a hierarchical approach; runs iteratively until the lowest-energy
structures are achieved and then uses publicly available function
information to identify closely related templates with the same function
|
Features: Good and easy-to-use web tool and a powerful standalone tool
|
|
Limitations: Lacks accuracy when few templates are available and is
slower than similar options available
|
| Modeller |
Protein structure modeling tool that predicts structures by the
satisfaction of spatial restraints obtained from a sequence alignment
and shown as a probability-density function
|
Features: Can be installed on any platform and is very fast in creating
a new model
|
|
Limitations: Speed comes at the cost of accuracy for models where slower
tools yield better results
|
| Multiple sequence alignment (MSA) |
Clustal Omega |
Multiple sequence alignment web tool |
Features: Has been constantly developed since the 1980s for MSA |
|
Limitations: Does not yield good results when a large amount of
sequences is provided as input
|
|
Multiple Alignment Using Fast Fourier Transform (MAFFT)
|
Multiple sequence alignment web tool; can also be used locally as a
standalone tool
|
Features: Users can choose between various multiple alignment methods
|
| Limitations: It requires more memory to run |
|
Multiple Sequence Comparison by Log-Expectation (MUSCLE)
|
Multiple sequence alignment web tool; as with Clustal Omega, it is
integrated in the EBI ecosystem
|
Features: Can achieve better average accuracy and speed than ClustalW2
or T-Coffee
|
|
Limitations: The Kimura distance used at the second stage, although
fast, does not consider which changes of amino acids occur between
sequences
|
| Protein design |
AbDesign |
An algorithm for backbone design using structure- and sequence-based
information
|
Features: Stepwise workflow for the design of antibodies that focuses on
stability and binding affinity
|
|
Limitations: Requires sufficient sequence data on homologs as well as
atomic coordinates
|
| FuncLib |
Web tool to design and rank multiple point mutations based on
evolutionary information and protein-folding stability calculations
|
Features: Multipoint variant design tool with an easy-to-use web server
|
|
Limitations: Works better with a pre-stabilized protein scaffold; poor
knowledge of one's system may lead to poor results
|
| Loop Grafter |
A web tool with a workflow to compare loop dynamics between proteins and
transplant loops from one protein to another
|
Features: Automated way to transfer loops from one protein to the other
|
|
Limitations: Works only with the input of both the template and the
scaffold proteins
|
| PROSS |
A user-friendly web tool to predict protein amino acid substitutions
that yield higher-stability variants
|
Features: Automated way to stabilize proteins by inserting mutations in
the original protein; the method is reliable enough that only a more
limited number of designs as output is sufficient
|
|
Limitations: Requires a structure (which may not always be available)
for stability calculations
|
| ProtLego |
A Python library for chimera design and analysis |
Features: Automatic construction and ranking of chimeras |
|
Limitations: The correlation between structural features and
experimental success is not yet clear
|
| Rosetta |
A comprehensive software suite with several algorithms that can be used
for the modeling and analysis of proteins
|
Features: Encompasses many modules under the same umbrella name |
|
Limitations: Not unified and developed by many people through the years;
can be hard to implement and use different modules
|
| SEWING |
A protocol to design new tertiary protein structures by 'sewing'
together secondary-structure building blocks
|
Features: Continuous and discontinuous SEWING can be merged to create
additional diversity
|
|
Limitations: At present, it appears to have been applied only to the
construction of all-α-helix chimeras
|
| Tunnels and cavities |
CAVER |
Software tool for the analysis and visualization of tunnels and channels
in protein structure
|
Features: Integration with other CaverSuite tools allows deeper analysis
|
| Limitations: Still lacks the possibility of calculating pores |
| POVME |
Standalone tool for ligand-binding pocket calculations
|
Features: Calculates ligand-binding pockets using MD snapshots |
|
Limitations: The lack of a GUI makes it less accessible to
non-bioinformaticians
|
| Similarity search |
BLAST |
A tool to calculate statistical significance between biological
sequences
|
Features: One of the most-used tools for local alignment search; fast
and easy to use
|
|
Limitations: Developed in 1990 and has not changed substantially since
then
|
| FASTA |
A web tool to provide a heuristic local search with a protein query
|
Features: First tool in the field; as with any other tool from the EBI,
it is integrated with many other tools and analyses; newer tools exist
that have evolved from this
|
|
Limitations: As opposed to BLAST, it does not remove low-complexity
regions
|
| Structure and trajectory data |
Bio3D |
R package for the analysis of protein structure and trajectory data;
provides a variety of approaches for conformational analysis of a
protein
|
Features: Comprehensive tool with many tutorials and easy installation
|
|
Limitations: Lack of GUI and a webserver makes for a steep learning
curve for non-bioinformaticians
|
Figure 1. Enzyme De Novo Design. (Zanghellini A.2014)
