SSEThread

SSEThread assigns polypeptide sequences to structural maps by integratively threading sequences against experimental and prior structural data to resolve ambiguous sequence registration in regions where X-ray crystallography and electron microscopy maps (3-8 Å) are insufficient.

Key Features:

• Integrative data use: Formulates sequence threading as an optimization problem that integrates chemical cross-linking, hydrogen deuterium exchange (HDX), prior structural models, and sequence connectivity.
• Handles ambiguous maps: Resolves ambiguous sequence registration on polypeptide chains derived from X-ray crystallography and electron microscopy maps at ~3-8 Å resolution.
• Optimization framework: Implements a system representation of structural and biophysical properties, a flexible scoring function within the Integrative Modeling Platform (IMP), and optimization algorithms to explore configurations.
• Ensemble generation: Produces ensembles of threading models to represent structural dynamics and alternative sequence assignments.
• Application example: Applied to a 199-residue disordered region of DNA-PKcs using chemical crosslinks, HDX, and sequence connectivity to generate threading model ensembles.
• Biological insight extraction: Enables inference of conformational rearrangement hypotheses such as reorganization of the ABCDE cluster of phosphorylation sites in DNA-PKcs required for intra-molecular autophosphorylation.

Scientific Applications:

• Structure-function of disordered regions: Elucidates sequence registration and structural models for proteins with disordered or ambiguous regions.
• Conformational dynamics: Investigates conformational rearrangements relevant to mechanisms such as autophosphorylation within the ABCDE cluster of DNA-PKcs.
• Integrative model refinement: Enhances accuracy of models derived from partial structural data by integrating chemical cross-linking, HDX, and prior models.

Methodology:

SSEThread models sequence threading as an optimization problem that integrates chemical cross-linking, hydrogen deuterium exchange (HDX), prior structural models, and sequence connectivity; it uses a system representation, a flexible scoring function implemented in the Integrative Modeling Platform (IMP), and optimization algorithms to explore configurations and generate ensembles of threading models.