A toolkit and benchmark study for FRET-restrained high-precision structural modeling

Stanislav Kalinin; Thomas Peulen; Simon Sindbert; Paul J. Rothwell; Sylvia Berger; Tobias Restle; Roger S. Goody; Holger Gohlke; Claus A.M. Seidel

doi:10.1038/nmeth.2222

A toolkit and benchmark study for FRET-restrained high-precision structural modeling

Stanislav Kalinin^*, Thomas Peulen, Simon Sindbert, Paul J. Rothwell, Sylvia Berger, Tobias Restle, Roger S. Goody, Holger Gohlke, Claus A.M. Seidel

^*Corresponding author for this work

Institute of Molecular Medicine

153 Citations (Scopus)

Abstract

We present a comprehensive toolkit for Förster resonance energy transfer (FRET)-restrained modeling of biomolecules and their complexes for quantitative applications in structural biology. A dramatic improvement in the precision of FRET-derived structures is achieved by explicitly considering spatial distributions of dye positions, which greatly reduces uncertainties due to flexible dye linkers. The precision and confidence levels of the models are calculated by rigorous error estimation. The accuracy of this approach is demonstrated by docking a DNA primer-template to HIV-1 reverse transcriptase. The derived model agrees with the known X-ray structure with an r.m.s. deviation of 0.5 Å. Furthermore, we introduce FRET-guided 'screening' of a large structural ensemble created by molecular dynamics simulations. We used this hybrid approach to determine the formerly unknown configuration of the flexible single-strand template overhang.

Original language	English
Journal	Nature Methods
Volume	9
Issue number	12
Pages (from-to)	1218-1225
Number of pages	8
ISSN	1548-7091
DOIs	https://doi.org/10.1038/nmeth.2222
Publication status	Published - 01.12.2012

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10.1038/nmeth.2222

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title = "A toolkit and benchmark study for FRET-restrained high-precision structural modeling",

abstract = "We present a comprehensive toolkit for F{\"o}rster resonance energy transfer (FRET)-restrained modeling of biomolecules and their complexes for quantitative applications in structural biology. A dramatic improvement in the precision of FRET-derived structures is achieved by explicitly considering spatial distributions of dye positions, which greatly reduces uncertainties due to flexible dye linkers. The precision and confidence levels of the models are calculated by rigorous error estimation. The accuracy of this approach is demonstrated by docking a DNA primer-template to HIV-1 reverse transcriptase. The derived model agrees with the known X-ray structure with an r.m.s. deviation of 0.5 {\AA}. Furthermore, we introduce FRET-guided 'screening' of a large structural ensemble created by molecular dynamics simulations. We used this hybrid approach to determine the formerly unknown configuration of the flexible single-strand template overhang.",

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AU - Kalinin, Stanislav

AU - Peulen, Thomas

AU - Sindbert, Simon

AU - Rothwell, Paul J.

AU - Berger, Sylvia

AU - Restle, Tobias

AU - Goody, Roger S.

AU - Gohlke, Holger

AU - Seidel, Claus A.M.

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AB - We present a comprehensive toolkit for Förster resonance energy transfer (FRET)-restrained modeling of biomolecules and their complexes for quantitative applications in structural biology. A dramatic improvement in the precision of FRET-derived structures is achieved by explicitly considering spatial distributions of dye positions, which greatly reduces uncertainties due to flexible dye linkers. The precision and confidence levels of the models are calculated by rigorous error estimation. The accuracy of this approach is demonstrated by docking a DNA primer-template to HIV-1 reverse transcriptase. The derived model agrees with the known X-ray structure with an r.m.s. deviation of 0.5 Å. Furthermore, we introduce FRET-guided 'screening' of a large structural ensemble created by molecular dynamics simulations. We used this hybrid approach to determine the formerly unknown configuration of the flexible single-strand template overhang.

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A toolkit and benchmark study for FRET-restrained high-precision structural modeling

Abstract

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