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Improvements in comparative protein structure modeling for the remote target-template sequence similarity cases are possible through the optimal combination of multiple template structures and by improving the quality of target-template alignment. Here we describe new developments in both the alignment generation and the template selection parts of the modeling algorithms.

We set up a new scoring function in MMM to deliver more accurate target-template alignments. This was achieved by developing and incorporating into the composite scoring function a novel statistical pairwise potential that combines local and non-local terms. The non-local term of the statistical potential utilizes a shuffled reference state definition that helped to eliminate most of the false positive signal from the background distribution of pairwise contacts.

A key aim of the worldwide structural genomics efforts is the experimental solution of the three dimensional structures of a carefully selected few thousand target sequences of structurally uncharacterized proteins. Subsequently these newly solved structures will be used as templates for computational modeling of about 10— times more proteins whose sequences are related [ 1 ]. Homology modeling proved to be the most accurate approach for protein structure prediction provided that a three dimensional structure of a sequentially similar template protein exist [ 3 — 9 ].

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