Bioinformatics 18: Structural 3

Question 1

Describe the single step approach of homology modelling. What software uses this?

Answer 1

Used by MODELLER
Target sequence is mapped onto template 3D structure

Spatial features (e.g. dihedral angles, hydrogen bonds) transferred from template to target

Individual structure features represented as probability functions (used as restraints in model construction)

-> family of models produced consistent with these functions

Question 2

Describe the fragment based approach of homology modelling. What software uses this?

Answer 2

Used by SWISSMODEL
Build well defined polypeptide backbone - tend to be secondary structural elements

Join these fragments with less well defined regions of polypeptide backbond - tend to be ‘loops’

Place amino acid side chains

Refine model

Question 3

How do you ‘refine’ a homology model?

Answer 3

Consider:
Energy minimisation
Molecular Dynamics
Simulated annealing (all global)

Optimisation with side chain rotamer libraries (local)

Loop modelling, loop libraries (local)

Question 4

Factors to consider when determining how valid a model is?

Answer 4

Sequence identity indicator for model quality (alignment)

How well do models agree/fit with experimental data? e.g. from site directed mutagenesis studies

Health checks: Bonds, bond angles, dihedral angles, energy scores etc. - check with WhatCheck

Packing and non-bonding contacts

Control models (compare to similar existing protein structures)

Question 5

What is CASP?

Answer 5

Critical assessment of methods of protein structure prediction