(Georgia Institute of Technology, 2008-12-12)
Pandit, Shashi Bhushan; Skolnick, Jeffrey
Background: Protein tertiary structure comparisons are employed in various fields of
contemporary structural biology. Most structure comparison methods involve generation of an
initial seed alignment, which is extended and/or refined to provide the best structural superposition
between a pair of protein structures as assessed by a structure comparison metric. One such
metric, the TM-score, was recently introduced to provide a combined structure quality measure
of the coordinate root mean square deviation between a pair of structures and coverage. Using the
TM-score, the TM-align structure alignment algorithm was developed that was often found to have
better accuracy and coverage than the most commonly used structural alignment programs;
however, there were a number of situations when this was not true.
Results: To further improve structure alignment quality, the Fr-TM-align algorithm has been
developed where aligned fragment pairs are used to generate the initial seed alignments that are
then refined using dynamic programming to maximize the TM-score. For the assessment of the
structural alignment quality from Fr-TM-align in comparison to other programs such as CE and TMalign,
we examined various alignment quality assessment scores such as PSI and TM-score. The
assessment showed that the structural alignment quality from Fr-TM-align is better in comparison
to both CE and TM-align. On average, the structural alignments generated using Fr-TM-align have
a higher TM-score (~9%) and coverage (~7%) in comparison to those generated by TM-align. Fr-
TM-align uses an exhaustive procedure to generate initial seed alignments. Hence, the algorithm is
computationally more expensive than TM-align.
Conclusion: Fr-TM-align, a new algorithm that employs fragment alignment and assembly provides
better structural alignments in comparison to TM-align. The source code and executables of Fr-
TM-align are freely downloadable at: http://cssb.biology.gatech.edu/skolnick/files/FrTMalign/.
(Georgia Institute of Technology, 2006-12)
Pandit, Shashi Bhushan; Zhang, Yang; Skolnick, Jeffrey
This study involves the development of a rapid comparative modeling tool for homologous sequences by extension of the TASSER methodology, developed for tertiary structure prediction. This comparative modeling procedure was validated on a representative benchmark set of proteins in the Protein Data Bank composed of 901 single domain proteins (41- 200 residues) having sequence identities between 35-90% with respect to the template. Using a Monte Carta search scheme with the length of runs optimized lor weakly/nonhomologous proteins, TASSER often provides appreciable improvement in structure quality over the initial template. However, on average, this requires - 29 h of CPU time per sequence. Since homologous proteins are unlikely to require the extent of conformational search as weakly/nonhomologous proteins, TASSER's parameters were optimized to reduce the required CPU time to - 17 min, while retaining TASSER's ability to improve structure quality. Using this optimized TASSER (T ASSER-Lite), we find an average improvement in the aligned region of - 10% in root mean-square deviation from native over the initial template. Comparison of TASSER-Lite with the widely used comparative modeling tool MODELLER showed that TASSER-Lite yields final models that are closer to the native. TASSER-Lite is provided on the web at http://cssb.biology.gatech.edulskolnicklwebserviceltassertiteflndex.html.