The HHpred interactive server for protein homology detection and structure prediction

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Automated protein structure prediction is becoming a mainstream tool for biological research. This has been fueled by steady improvements of publicly available automated servers over the last decade, in particular their ability to build good homology models for an increasing number of targets by reliably detecting and aligning more and more remotely homologous templates.

HHpred is a fast server for remote protein homology detection and structure prediction and is the first to use pairwise comparison of profile hidden Markov models (HMMs). It allows to search a wide choice of databases, such as the PDB, SCOP, Pfam, SMART, COGs and CDD. It accepts a single query sequence or a multiple alignment as input. Within only a few minutes it returns the search results in a user-friendly format similar to that of PSI-BLAST. Search options include local or global alignment and scoring secondary structure similarity. HHpred can produce pairwise query-template alignments, multiple alignments of the query with a set of templates selected from the search results, as well as 3D structural models that are calculated by the MODELLER software from these alignments. A search through the PDB database of proteins with solved 3D structure takes a few minutes. If a significant match with a protein of known structure (a "template") is found in the PDB database, HHpred allows the user to build a homology model using the MODELLER software, starting from the pairwise query-template alignment.

The output of HHpred is a ranked list of database matches (including E-values and probabilities for a true relationship) and the pairwise query-database sequence alignments. HHpred servers have been ranked among the best servers during CASP7, 8, and 9, for blind protein structure prediction experiments.

HHpred belongs to the class of profile-profile comparison tools, which includes the most sensitive sequence search methods to date. They show both the query sequence and the database sequences by sequence profiles, also called position-specific scoring matrices (PSSMs). Profiles are calculated from a multiple sequence alignment of related sequences which are collected, for example, using the PSI-BLAST program or the HHblits program from the HH-suite package. A profile is a matrix containing for each position in the query sequence the similarity score for the 20 amino acids. These scores are calculated from the frequencies of the amino acids at the corresponding positions in the multiple sequence alignment. Search options include local or global alignment and scoring secondary structure similarity.


  • protein sequence alignment tool

  • protein structure alignment tool

  • multiple sequence alignment

  • protein homology detection

  • protein structure prediction tool

  • complex structure prediction

  • function prediction

  • domain prediction

  • domain boundary prediction

  • evolutionary classification of proteins

  • Build a multiple sequence alignment for the target sequence

  • Search for homologous templates

  • Re‐rank the potential templates with a neural network Generate sets of multiple alignments with successively lower sequence diversities for the target sequence and the templates

  • Rank target‐template alignments of various alignment diversities with neural network

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