Rappertk: a versatile engine for discrete restraint-based conformational sampling of macromolecules

BackgroundMacromolecular structures are modeled by conformational optimization within experimental and knowledge-based restraints. Discrete restraint-based sampling generates high-quality structures within these restraints and facilitates further refinement in a continuous all-atom energy landscape. This approach has been used successfully for protein loop modeling, comparative modeling and electron density fitting in X-ray crystallography.ResultsHere we present a software toolkit (Rappertk) which generalizes discrete restraint-based sampling for use in structural biology. Modular design and multi-layered architecture enables Rappertk to sample conformations of any macromolecule at many levels of detail and within a variety of experimental restraints. Performance against a Cα-tracing benchmark shows that the efficiency has not suffered despite the overhead required by this flexibility. We demonstrate the toolkit's capabilities by building high-quality β-sheets and by introducing restraint-driven sampling. RNA sampling is demonstrated by rebuilding a protein-RNA interface. Ability to construct arbitrary ligands is used in sampling protein-ligand interfaces within electron density. Finally, secondary structure and shape information derived from EM are combined to generate multiple conformations of a protein consistent with the observed density.ConclusionThrough its modular design and ease of use, Rappertk enables exploration of a wide variety of interesting avenues in structural biology. This toolkit, with illustrative examples, is freely available to academic users from http://www-cryst.bioc.cam.ac.uk/~swanand/mysite/rtk/index.html.

• Publication year

  2007

• Venue

  BMC Structural Biology

• Publication date

  2007-03-21

• Fields of study

  Biology, Medicine, Chemistry, Computer Science

• Identifiers
  DOI 10.1186/1472-6807-7-13PMID 17376228PMCID 1847436
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Bent out of shape: RNA unwinding by the DEAD-box helicase Vasa.

  2006cited by this paper
• Knowledge-based real-space explorations for low-resolution structure determination.

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• Conformer generation under restraints.

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• Automated ligand placement and refinement with a combined force field and shape potential.

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• Structural basis for RNA unwinding by the DEAD-box protein Drosophila Vasa.

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