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A restraint molecular dynamics and simulated annealing approach for protein homology modeling utilizing mean angles

Andreas Möglich12, Daniel Weinfurtner13, Till Maurer14, Wolfram Gronwald1 and Hans Robert Kalbitzer1*

Author Affiliations

1 Institut für Biophysik und physikalische Biochemie, Universität Regensburg, Universitätsstr. 31, D-93053 Regensburg, Germany

2 Department of Biophysical Chemistry, Biozentrum, University of Basel, Klingelbergstr. 70, CH-4056 Basel, Switzerland

3 Institut für Organische Chemie und Biochemie, Technische Universität München, Lichtenbergstr. 4, D-85747 Garching, Germany

4 Department of Lead Discovery, Boehringer Ingelheim Pharma GmbH, Birkendorfer Str. 65, D-88397 Biberach, Germany

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BMC Bioinformatics 2005, 6:91  doi:10.1186/1471-2105-6-91

Published: 8 April 2005

Abstract

Background

We have developed the program PERMOL for semi-automated homology modeling of proteins. It is based on restrained molecular dynamics using a simulated annealing protocol in torsion angle space. As main restraints defining the optimal local geometry of the structure weighted mean dihedral angles and their standard deviations are used which are calculated with an algorithm described earlier by Döker et al. (1999, BBRC, 257, 348–350). The overall long-range contacts are established via a small number of distance restraints between atoms involved in hydrogen bonds and backbone atoms of conserved residues. Employing the restraints generated by PERMOL three-dimensional structures are obtained using standard molecular dynamics programs such as DYANA or CNS.

Results

To test this modeling approach it has been used for predicting the structure of the histidine-containing phosphocarrier protein HPr from E. coli and the structure of the human peroxisome proliferator activated receptor γ (Ppar γ). The divergence between the modeled HPr and the previously determined X-ray structure was comparable to the divergence between the X-ray structure and the published NMR structure. The modeled structure of Ppar γ was also very close to the previously solved X-ray structure with an RMSD of 0.262 nm for the backbone atoms.

Conclusion

In summary, we present a new method for homology modeling capable of producing high-quality structure models. An advantage of the method is that it can be used in combination with incomplete NMR data to obtain reasonable structure models in accordance with the experimental data.