TY  - THES
T1  - Free energy prediction of biomolecular systems using ensembles of structures
A1  - Benedix,Alexander
Y1  - 2009/11/06
N2  - Knowledge about the underlying free energy landscape of biomolecules is crucial for a basic understanding of the inner workings of proteins. Its fast and accurate calculation is indispensable for conformational analysis, structure-based protein design or for protein docking. On the one hand, existing rigorous methods like free energy perturbation or thermodynamic integration are time-consuming and cannot be used for large scans required for protein or vaccine design. On the other hand, fast treatments rely on empirical or statistical data and deliberately neglect protein flexibility and are therefore limited in accuracy.
In this thesis, a novel method for the estimation of free energy changes upon mutation is proposed combining a physical effective energy function with an efficient sampling of available conformational space. The energy function is based on physical chemistry and an efficient continuum solvent approach. It is averaged over alternative protein conformations fulfilling geometric constraints. The main advantage of our method is its inclusion of full protein flexibility, which dramatically improves the prediction quality for protein-protein binding affinities. Due to its hundredfold gain in speed with respect to conventional methods the method enables e.g. full mutant scanning of protein-protein interfaces.
The method was successfully applied to the study of mutational effects on protein-protein and protein-peptide binding.
KW  - Freie Energie
KW  - Molekulardynamik
KW  - Proteinfaltung
KW  - Proteinbindung
KW  - Insulin
KW  - Protein p53
KW  - Lactamase <beta->
CY  - Saarbrücken
PB  - Universitäts- und Landesbibliothek
AD  - Postfach 151141, 66041 Saarbrücken
UR  - http://scidok.sulb.uni-saarland.de/volltexte/2009/2540
ER  -