Download Question 1 - University of Missouri

Discussion of Protein Disorder
Prediction
Jianlin Cheng
University of Missouri, Columbia, MO, USA
(MULTICOM-CMFR & MULITCOM)
Question 1
In you analysis of disorder do you treat short
disordered regions, e.g. a missing loop in a
crystal structure, differently than a disordered
domain or an entirely disordered protein?
No. Two reasons (laziness and principle)
Question 2
Can you briefly describe your disorder analysis,
i.e. is it based on physical principals, machine
learning or a combination of both?
Machine learning – 1D-Recursive Neural
Network
Input: sequence profile, predicted secondary
structure, relative solvent accessibility
Output: disorder (+), order (-)
Question 3
Does your analysis of disorder prediction affect
your template free modeling, i.e. does the
disorder prediction aid your free model
prediction? If so, in what way, in practice, did you
use your disorder prediction for free modeling?
Occasionally. T0500 (800 residues)
Should be useful for both template-based and
template-free modeling
Question 4
Can your disorder prediction distinguish
between regions predicted to be fully
disordered, i.e. 'cooked spaghetti', or
alternatively an ensemble of a few alternative
conformations?
Maybe. Strength of signal?
Disorder Ensemble
• Some disorder regions may be not fully
disordered.
• Most likely a discrete distribution of a number
of conformations
• Disorder regions switch from one
conformation to another according to
probability
NMR to Determine Ensemble
Conformations
New NMR techniques can gather local
conformations and long-range interactions
even under strongly denaturing conditions to
obtain plausible all-atom models of the
unfolded state at increasing accuracy.
S. Meier et al. J. Chemical Physics, 2008
Energy Landscape of Ordered
Globular Protein
Chan and Dill, Nature Structure Biology, 1997
Energy Landscape of Disordered
Regions
Shallow, unstable energy
landscape
Contacts in Ensemble
• Essential contacts (conserved long-range
interactions)
• Non-essential contacts (transient contacts)
• How to predict essential contacts?
Prediction of Ensemble
• Protein conformation space is significantly
reduced due to essential contacts
• Predict ensemble conformations using
template-free modeling
• Predict ensemble conformations using
constrained molecular dynamics