Predicting Protein 3D Structure

Basic Information

Christopher Burge, David Gifford, and Ernest Fraenkel. 7.91J Foundations of Computational and Systems Biology. Spring 2014. Massachusetts Institute of Technology: MIT OpenCourseWare, https://ocw.mit.edu. License: Creative Commons BY-NC-SA.

• MIT 7.91J Foundations of Computational and Systems Biology🌎
• Lecture 13

• MIT OpenCourseWare
• YouTube Link

Homology

Rosetta

• Align query to sequences in PDB
• Use several alignment methods
• Three categories of queries
  • High sequence similarity template(s) (>50% sequence similarity)
  • Medium sequence similarity template(s) (20-50% sequence similarity)
  • Low sequence similarity template(s) (<20% sequence similarity)
• Refine models

General Refinement Procedure

• Random changes to backbone torsion angles
• Rotamer optimization of side chains
• Energy minimization of torsion angles (bond lengths and angles kept fixed)

High sequence similarity template(s)

• Minimal refinement, focus on regions where alignment is poor
• Refine structures
• Choose best model by final energy

Medium sequence similarity template(s)

• Refinement focuses on regions near gaps and insertions, loops in the starting model, and sequence segments with low conservation
• Replaces torsion angles with those from peptides of known structures
• Minimize local structure
• Refine global structure

Low sequence similarity template(s)

• Use many more starting models
• More aggressive refinement strategy
  • Rebuild secondary structure elements in addition to regions refined in medium homology
    • gaps and insertions
    • loops in the starting model
    • regions with low conservation

de novo

Rosetta

When there is no suitable homology model:

• Monte Carlo search for backbond angles
  • Choose a short region (3-9 amino acids, Empirical) of backbone
  • Set torsion angles to those of a similar peptide in PDB
  • Accept with Metropolis Criteria
• 36,000 MC steps
• Repeat entire process to get 2,000 final structures
• Cluster structures
• Refine clusters