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What is HH-suite?

HH-suite is an open-source software package for sensitive protein sequence searching based on the pairwise alignment of hidden Markov models (HMMs). It’s designed to detect remote homology relationships that traditional sequence-to-sequence comparison methods often miss.
HH-suite3 is maintained by the Söding Lab at the Max Planck Institute for Biophysical Chemistry and is widely used in structural biology, protein function prediction, and evolutionary studies.

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Key Features

HMM-HMM Comparison

Uses profile-to-profile alignment for significantly improved sensitivity compared to sequence-based methods

Fast Performance

Optimized implementations with SSE2/AVX2 support and optional MPI parallelization

Multiple Tools

Includes hhblits, hhsearch, hhmake, hhalign, and more for various workflows

Large Databases

Compatible with Uniclust, BFD, Pfam, SCOP, PDB70, and custom databases

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How HMM-HMM Comparison Works

Traditional sequence comparison methods compare individual sequences, but HH-suite takes a more powerful approach:
1

Build Query Profile

Convert your query sequence into a Hidden Markov Model (HMM) that represents evolutionary information from related sequences
2

Compare Profiles

Align your query HMM against target HMMs from a database, capturing position-specific amino acid preferences
3

Score Matches

Calculate alignment scores and statistical significance (E-values) to identify homologous proteins
This profile-to-profile approach dramatically increases sensitivity for detecting remote evolutionary relationships.

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Main Programs

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hhblits

Iterative profile search against sequence databases. Fast and sensitive for building multiple sequence alignments. 
hhblits -i query.fasta -o results.hhr -d database

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hhsearch

Search with a query profile against a database of HMM profiles. Ideal for finding remote homologs in well-curated databases like PDB70 or Pfam. 
hhsearch -i query.a3m -d pdb70 -o results.hhr

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hhmake

Build HMM profiles from multiple sequence alignments. 
hhmake -i alignment.a3m -o profile.hhm

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hhalign

Align two HMMs or profiles for detailed comparison. 
hhalign -i query.hhm -t target.hhm -o alignment.hhr

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Use Cases

HH-suite excels at tasks requiring detection of distant evolutionary relationships.
  • Protein Structure Prediction: Find templates for homology modeling
  • Functional Annotation: Infer function by detecting remote homologs with known functions
  • Evolutionary Studies: Trace protein family relationships across deep evolutionary time
  • Metagenomics: Annotate novel proteins from environmental samples
  • Domain Architecture: Identify conserved domains in multi-domain proteins

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System Requirements

HH-suite3 requires:
  • 64-bit system (Linux, macOS, or WSL on Windows)
  • SSE2 instruction set (AVX2 recommended for ~2x speedup)
  • Support for ARM64 and PPC64LE architectures on Linux
Check your CPU capabilities with cat /proc/cpuinfo | grep sse2 on Linux or sysctl -a | grep machdep.cpu.features | grep SSE2 on macOS.

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Version Information

The current version is HH-suite 3.3.0, which includes performance improvements, better handling of large databases, and enhanced multithreading support.

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Citation

If you use HH-suite in your research, please cite:
Steinegger M, Meier M, Mirdita M, Vöhringer H, Haunsberger S J, and Söding J (2019) HH-suite3 for fast remote homology detection and deep protein annotation, BMC Bioinformatics, 473. doi: 10.1186/s12859-019-3019-7

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Next Steps

Installation

Install HH-suite via conda, Docker, or from source

Quick Start

Run your first protein search in minutes

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