Improvement of comparative model accuracy by free-energy optimization along principal components of natural structural variation

TitleImprovement of comparative model accuracy by free-energy optimization along principal components of natural structural variation
Publication TypeJournal Article
Year of Publication2004
AuthorsQian, B., Ortiz A. R., & Baker D.
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue43
Pagination15346-51
Date Published2004 Oct 26
ISSN0027-8424
KeywordsModels, Molecular, Primary Publication, Protein Conformation
Abstract

Accurate high-resolution refinement of protein structure models is a formidable challenge because of the delicate balance of forces in the native state, the difficulty in sampling the very large number of alternative tightly packed conformations, and the inaccuracies in current force fields. Indeed, energy-based refinement of comparative models generally leads to degradation rather than improvement in model quality, and, hence, most current comparative modeling procedures omit physically based refinement. However, despite their inaccuracies, current force fields do contain information that is orthogonal to the evolutionary information on which comparative models are based, and, hence, refinement might be able to improve comparative models if the space that is sampled is restricted sufficiently so that false attractors are avoided. Here, we use the principal components of the variation of backbone structures within a homologous family to define a small number of evolutionarily favored sampling directions and show that model quality can be improved by energy-based optimization along these directions.

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
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