Homology modeling using parametric alignment ensemble generation with consensus and energy-based model selection.

Abstract:

:The accuracy of a homology model based on the structure of a distant relative or other topologically equivalent protein is primarily limited by the quality of the alignment. Here we describe a systematic approach for sequence-to-structure alignment, called 'K*Sync', in which alignments are generated by dynamic programming using a scoring function that combines information on many protein features, including a novel measure of how obligate a sequence region is to the protein fold. By systematically varying the weights on the different features that contribute to the alignment score, we generate very large ensembles of diverse alignments, each optimal under a particular constellation of weights. We investigate a variety of approaches to select the best models from the ensemble, including consensus of the alignments, a hydrophobic burial measure, low- and high-resolution energy functions, and combinations of these evaluation methods. The effect on model quality and selection resulting from loop modeling and backbone optimization is also studied. The performance of the method on a benchmark set is reported and shows the approach to be effective at both generating and selecting accurate alignments. The method serves as the foundation of the homology modeling module in the Robetta server.

journal_name

Nucleic Acids Res

journal_title

Nucleic acids research

authors

Chivian D,Baker D

doi

10.1093/nar/gkl480

subject

Has Abstract

pub_date

2006-01-01 00:00:00

pages

e112

issue

17

eissn

0305-1048

issn

1362-4962

pii

gkl480

journal_volume

34

pub_type

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