Download eGOR Predicting the total potential Energy of a Protein`s native State

eGOR
Predicting the total potential Energy of a Protein’s native
State by Sequence
Florian Heinke, Steffen Grunert and Dirk Labudde
University of Applied Sciences, Technikumplatz 17, D-09648 Mittweida
Methods
Background and Motivation
Predicting Protein Energy Profiles
• Established methods for predicting/modeling protein structures:
• comparative (homology) modeling
• fragment library-based modeling (i.e. MODELLER, ROBETTA)
• ab initio folding [1,6]
Protein Sequence
eGOR
• Drawbacks of these methods are:
• necessity of structural template(s)
• computational and time-demanding
• energy guidance values of the native state are unknown [1,3,6]
•adapted GOR algorithm [2]
•prediction of discretized energy
profiles
•based on information theory
•Correlation: Etot,MD ~ Etot,predicted
R² = 0.96
Energy profile of trpCage
• predicted from sequence
• calculated from structure
Methods
Computing Protein Energy Profiles
ETot can be predicted from
sequence accurately
5
0
1
Ei [a.u.]
-5
Residue-residue interaction
3
5
7
9
11
13
15
17
ETot,MD
= 1,111 kcal/mol
-10
ETot,predicted = 1,266 kcal/mol
-15
-20
-25
-30
Coarse-grained energy
residue index
Application and Conclusions
Case study: Ab initio folding simulation of TrpCage
Residue-residue interactions in trpCage (PDB ID: 2JOF)
1400
1300
(2)
Etot,MD [kcal/mol]
(1)
(3)
Energy profile of trpCage
5
Ei [a.u.]
ETot,MD > ETot,predicted
Plausibility predicted by eGOR
1200
t = 50 ns
1100
1000
t = 25 ns
900
800
0
-5
structures with ETot,MD ≈ ETot,predicted
1
3
5
7
9
11
13
15
t = 1 ns
700
17
0
5
10
RMSD to native state [Ǻ]
15
-10
-15
-20
Conclusions
residue index
[3,5]
Correlation to total potential energies derived from
molecular dynamics [4]
 calculated from 220 glob. protein
structures
ETot,MD
 energy profiles can be predicted from sequence by eGOR
 from these, total pot. energy values ETot can be derived
 predicted ETot values correspond to ETot values observed in known protein
structures
 potential method for
• predicting ETot of an unknown protein structure
• protein structure assessment and concluding physical plausibility
• deriving guidance values for ab initio folding and protein structure
modeling
References
ETot
1 Peter L. Freddolino, Feng Liu, Martin Gruebele, and Klaus Schulten. Ten-microsecond molecular dynamics
simulation of a fast-folding WW domain. Biophys J, 94(10):L75-L77, May 2008.
2 J. Garnier, J. F. Gibrat, and B. Robson. GOR method for predicting protein secondary structure from amino acid
sequence. Methods Enzymol, 266:540-553, 1996.
3 Florian Heinke and Dirk Labudde. Membrane protein stability analyses by means of protein energy profiles in
case of nephrogenic diabetes insipidus. Comput Math Methods Med, 2012:790281, 2012.
4 J. Ponder. TINKER - software tools for molecular design. Technical report, Dept. of Biochemistry and Molecular
Biophysics, Washington University, School of Medicine, St. Louis, 2001.
5 S. Tanaka and H. A. Scheraga. Medium- and long-range interaction parameters between amino acids for
predicting three-dimensional structures of proteins. Macromolecules, 9(6):945-950, 1976.
6 M. Zvelebil and J.O. Baum. Understanding Bioinformatics. Garland Science,first edition, 2008.
contact: [email protected] [email protected]