Difference between revisions of "Homology modelling Gaucher Disease"

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The object of this task was to apply homology modelling for predicting the tertiary structure of glycosylceramidase given its [[https://i12r-studfilesrv.informatik.tu-muenchen.de/wiki/index.php/Gaucher_Disease#Sequence sequence]]. For this, we first selected different templates which were than used to derive the structure of glycosylceramidase using three different homology modeling tools, namely Modeller, SWISS-MODEL, and the I-TASSER server. The resulting models were evaluated using both quality assessment scores and the native crystal structure [http://www.rcsb.org/pdb/explore/explore.do?structureId=1OGS 1ogs]. Technical details are reported in our [[task04_protocol protocol].
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== Template selection ==
  
== Template selection ==
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We used HHsearch for searching the PDB for homologous templates. <xr id="templates"/> lists some of the top-ranking templates. 2nt0_A is identical to the target 1ogs_A and was therefore excluded. Although all listed hits are homologous to the target (HHsearch probability > 95%), their sequence identity was below 30%. We therefore selected 2wnw_A (blue) as a close homolog, 2y24_A (green) as an intermediate homolog, and 3nco_A (yellow) as a more distant homolog. Note that the latter two templates to not cover the complete target which makes the homology modeling process harder.
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<figtable id="tab:ss_mapping">
  
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<figtable id="tab:templates">
 
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Revision as of 19:53, 29 May 2012

The object of this task was to apply homology modelling for predicting the tertiary structure of glycosylceramidase given its [sequence]. For this, we first selected different templates which were than used to derive the structure of glycosylceramidase using three different homology modeling tools, namely Modeller, SWISS-MODEL, and the I-TASSER server. The resulting models were evaluated using both quality assessment scores and the native crystal structure 1ogs. Technical details are reported in our [[task04_protocol protocol].

Template selection

We used HHsearch for searching the PDB for homologous templates. <xr id="templates"/> lists some of the top-ranking templates. 2nt0_A is identical to the target 1ogs_A and was therefore excluded. Although all listed hits are homologous to the target (HHsearch probability > 95%), their sequence identity was below 30%. We therefore selected 2wnw_A (blue) as a close homolog, 2y24_A (green) as an intermediate homolog, and 3nco_A (yellow) as a more distant homolog. Note that the latter two templates to not cover the complete target which makes the homology modeling process harder. <figtable id="tab:templates">

Hit Nr Template Identity Query HMM Prob
> 80% sequence identity
1 2nt0_A 100.0 1-497 100.0
40% - 80% sequence identity
< 30% sequence identity
2 2wnw_A 28.0 36-496 100.0
3 3clw_A 14.0 64-495 100.0
4 2y24_A 18.0 66-495 100.0
5 3kl0_A 19.0 65-495 100.0
6 3zr5_A 17.0 65-494 100.0
7 3ik2_A 14.0 65-495 99.2
22 3nco_A 11.0 113-384 97.7
28 1egz_A 12.0 113-387 97.4

</figtable>

Modeller

Single-template modeling

2wnw_A
2y24_A
3nco_A
Dope score per residue.

<figtable id="tab:modeller_results">

Template DOPE DOPE z-score QMEAN6 RMSD TM-score GDT_TS GTD_HA
2wnw_A -55925 -0.471 0.689 1.006 0.824 0.661 0.479
2y24_A -47194 0.777 0.376 1.222 0.550 0.294 0.223
3nco_A -44033 1.224 0.139 2.158 0.252 0.093 0.043

</figtable>

Multiple-template modeling

2wnw_A-2y24_A-3kl0_A
2wnw_A-3nco_A
3ik2_A-3nco_A-1egz_A
Dope score per residue.

<figtable id="tab:modeller_results">

Template DOPE DOPE z-score QMEAN6 RMSD TM-score GDT_TS GTD_HA
2wnw_A-2y24_A-3kl0 -39084 1.930 0.314 1.987 0.465 0.277 0.179
2wnw_A-3nco_A -46962 0.807 0.556 1.256 0.778 0.593 0.409
3ik2_A-3nco_A-1egz_A -25391 0.3881 0.101 6.607 0.241 0.062 0.029

</figtable>

Using global HHsearch alignments

2wnw_A
2y24_A
3nco_A
2wnw_A
2y24_A
3nco_A
Dope score per residue.

<figtable id="tab:modeller-hhsearch-results">

Template DOPE DOPE z-score QMEAN6 RMSD TM-score GDT_TS GTD_HA
2wnw_A -54695 -0.295 0.726 1.079 0.869 0.732 0.538
2y24_A -47256 0.765 0.566 1.640 0.722 0.553 0.386
3nco_A -32577 2.857 0.272 9.757 0.398 0.235 0.131

</figtable>

Using local HHsearch alignments

2wnw_A
2y24_A
3nco_A
Dope score per residue.

<figtable id="tab:modeller-hhsearch-local-results">

Template DOPE DOPE z-score QMEAN6 RMSD TM-score GDT_TS GTD_HA
2wnw_A -53593 -0.744 0.749 1.003 0.866 0.731 0.532
2y24_A -46290 -0.030 0.564 1.162 0.724 0.563 0.381
3nco_A -25047 0.886 0.451 1.827 0.402 0.245 0.138

</figtable>

SWISS-MODEL

Automated mode

2wnw_A
2y24_A
3nco_A
Dope score per residue.

<figtable id="tab:modeller_results">

Template DOPE DOPE z-score QMEAN6 RMSD TM-score GDT_TS GTD_HA
2wnw_A -53863 -0.786 0.530 1.003 0.858 0.723 0.540
2y24_A -42674 0.565 0.430 1.100 0.712 0.539 0.382
3nco_A -27101 2.109 0.270 2.158 0.422 0.252 0.138

</figtable>

Alignment mode

2wnw_A
2y24_A
3nco_A
Dope score per residue.

<figtable id="tab:modeller_results">

Template DOPE DOPE z-score QMEAN6 RMSD TM-score GDT_TS GTD_HA
2wnw_A -53963 -0.788 0.540 1.011 0.859 0.722 0.536
2y24_A -40131 1.055 0.360 1.222 0.510 0.238 0.067
3nco_A -30244 0.689 0.240 2.001 0.426 0.247 0.135

</figtable>

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