Structure Prediction:Threading

The threading or "remote homology design" is a 3D structure prediction technique useful when there is no enough sequence simmilarity of the input sequence and a known 3D structure and, then, the "homology modeling" is not applicable. The process adapts the secuence to different known foldings and evaluate the fitting. The meaning of "fitting" varies from one threading program to others: secondary structure coincidence, simmilar accesibility or solvatation energy, etc..

Methods of protein fold recognition attempt to detect similarities between protein 3D structure that are not accompanied by any significant sequence similarity. There are many approaches, but the unifying theme is to try and find folds that are compatable with a particular sequence. Unlike sequence-only comparison, these methods take advantage of the extra information made available by 3D structure information. In effect, the turn the protein folding problem on it's head: rather than predicting how a sequence will fold, they predict how well a fold will fit a sequence.

Programs.

• 1.- The first step is to check that there isn't a homologous protein with known structure; it means, that it is not possible to use the homology modeling approach.  To answer this question, the first method to use is to run a  BLAST search against the PDB database.

• 2.- To study the secundary structure of the protein could help to evaluate the threading results: 1D characteristics.

• 3.- Some THREADING programs:

 
• Some links for methods that run via the WWW:

 
• 3D-pssm (ICNET). Based on sequence profiles, solvatation potentials and secondary structure.
• TOPITS (PredictProtein server) (EMBL). Based on coincidence of secondary structure and accesibility.
• UCLA-DOE Structure Prediction Server (UCLA). Executes various threading programs and report a consensus.
• 123D+. Combines substitution matrix, secondary structure prediction, and contact capacity potentials.
• SAM/HMM (UCSC). Basen on Markov models of alignments of crystalized proteins.
• FAS (Burnham Institute). Based on profile-profile matching algorithms of the query sequence with sequences from clustered PDB database.
• PSIPRED-GenThreader (Brunel)

 
• Methods where an executable or code is available:

 
• THREADER2(Warwick). Based on solvatation potentials and contacts obtained from crystalized proteins.
• ProFIT CAME (Salzburg)

• 4.- The classification/comparation 3D structure databases could help to analize the threading results: 3D databases: 3D structure databases.

• 5.- A good program to visualize and combine the Threading results:Threadlize

Practicals:

Some other sequences to try:

Protein 1. (Some threading servers results)

RLSWYDPDFQARLTRSNSKCQGQLEV YLKDGWHMVC 
SQSWGRSSKQWEDPSQASKVCQRLNCGVPLSLGPFLV
TYTPQSSIICYGQLGSFSNCSHSRNDMCHSLGLTCLE

Protein 2.

MAEDGPQKQQLEMPLVLDQDLTQQMRLRVESLKQRGEKKQDGEKLI 
RPAESVYRLDFIQQQKLQFDHWNVVLDKPGKVTITGTSQNWTPDLT 
NLMTRQLLDPAAIFWRKEDSDAMDWNEADALEFGERLSDLAKIRKV 
MYFLITFGEGVEPANLKASVVFNQL

Protein 3. (Some threading servers results)

MINRTDCNENSYLEIHNNEGRDTLCFANAGTMPVAIYGVNWVESGNNVVT
LQFQRNLSDPRLETITLQKWGSWNPGHIHEILSIRIY

Protein 4.

MIDLSKTVFYTSIDIGSRYIKGLVLGKRDQEWEALAFSSVKSRGLDEGEIKDAIAFKESV
NTLLKELEEQLQKSLRSDFVISFSSVSFEREDTVIERDFGEEKRSITLDILSEMQSEALE
KLKENGKTPLHIFSKRYLLDDERIVFNPLDMKASKIAIEYTSIVVPLKVYEMFYNFLQDT
VKSPFQLKSSLVSTAEGVLTTPEKDRGVVVVNLGYNFTGLIAYKNGVPIKISYVPVGMKH
VIKDVSAVLDTSFEESERLIITHGNAVYNDLKEEEIQYRGLDGNTIKTTTAKKLSVIIHA
RLREIMSKSKKFFREVEAKIVEEGEIGIPGGVVLTGGGAKIPRINELATEVFKSPVRTGC
YANSDRPSIINADEVANDPSFAAAFGNVFAVSENPYEETPVKSENPLKKIFRLFKELME

Protein 5.

VATAKYGTPVIDGEIDEIWNTTEEIERKAVAMGSLDKNAT 
AKVRVLWDENYLYVLAIVKDPVLNKDNSNPWEQDSVEIFI 
DENNHKTGYYEDDDAQFRVNYMNEQTFGTGGSPARFKTAV 
KLIEGGYIVEAAIKWKTIKPTPNTVIGFNIQVNDANEKGQ 
RVGIISWSDPTNNSWRDPSKFGNLRLIK