Integrative Structural Biology

Course goals

General learning goals
At the end of the course students will be able to:
- Use information from public repositories (e.g. ...Uniprot), scientific publication (e.g. ..eLife, etc.) and other structural biology tools (e.g. Alphafold3) to generate an integrative structural model
- Use validation reports to assess quality, reliability, and suitableness of particular findings or models of certain structures, domains, or regions for use in their own work
- Understand the limitations of specific models (segmentations, coordinates, distance restraints, predictions)
- Use various (online) software and visualisation tools for integrative modelling of biomolecular complexes 
- Combine structural results and predictions with functional data to generate holistic views of proteins and their complexes
- Relate structural information to the cellular context
- Summarize the strengths and weaknesses of different structural biology methods

Learning goals Cryo-EM
At the end of the course students will be able to:
- Use Q-score to judge reliability of particular residue, e.g. when designing mutants
- Assess agreement between density and derived/predicted models
- Build new atomic models from high resolution (<5 Angstrom) maps using automated tools
- Assess docking into low resolution (>5 Angstrom) maps, cross-validate with other methods
- Supplement density maps with dynamic/ensemble data to describe protein motions (e.g. ribosome translation landscape)

Learning goals Protein Crystallography
At the end of the course students will be able to:
- Evaluate the quality of published models from protein X-ray diffraction data
- Perform all steps in the refinement of a macromolecular model against the associated X-ray diffraction data, starting from published data
- Judge whether a conclusion based on X-ray diffraction data is justified considering the underlying data
- Identify differences in local agreement between electron density and a model 
- Provide an optimized model against X-ray diffraction data including a summary of the improved quality indicators
- Design a set of mutants with desired altered function, predicted from available structural biology data === general

Learning goals NMR
At the end of the course students will be able to:
- Evaluate the quality of published models from protein NMR data (structure/data)
- Perform NMR structure calculation, starting from research data from the group
- Be able to judge quality and information content of NMR interaction data in publications
- Value dynamical information from NMR data
- Be able to judge merits /limitations/requirements of NMR in protein complexes

Learning goals (Integrative) Modelling
At the end of the course students will be able to:
- Understand the concept of integrative modelling and how different data sources can be combined with modelling approaches to build 3D models of biomolecular assemblies
- Use AI tools to predict 3D structure and critically assess the quality of the generated models

Content

Several powerful structural biology tools are available to answer questions about the molecular mechanisms behind cellular function. Integrating information from these techniques can provide more insights than relying on one technique alone.
In the course Integrative Structural Biology, you will learn how to integrate the techniques and tools available to a modern-day structural biologist, using a hands-on approach to develop a deeper understanding of a biological system of study.

The course is split into two parts, theoretical and practical.
In the first 1.5 weeks, we will cover the strengths and limitations of datasets from the various experimental and computational techniques. The techniques to be covered will be, amongst other, Protein Crystallography, Cryogenic Electron Microscopy (Cryo-EM), Nuclear Magnetic Resonance (NMR), and (Integrative) Modelling. This theoretical section will be concluded with an exam.

In the second 1.5 weeks of the course, students will be split into groups in which they will work on a case study. This case study will be about a biological system of which information and structures from multiple techniques are available. Guided by this assignment, students will prepare a new integrated model and quality report. They will present their process and final result to their peers in a presentation.

Assessment methods
Test 50%
Presentation 30%
Assignment 20%