Applications are invited for a PhD student position available in the 
Computational Pharmaceutical Chemistry & Molecular Bioinformatics group 
(Prof. Dr. Holger Gohlke, http://cpclab.uni-duesseldorf.de) at the 
Heinrich-Heine-University, Duesseldorf, Germany, from April 1st, 2010.

Introduction. Understanding the relationship between microscopic structure 
and macroscopic stability is important for developing strategies to improve 
protein stability at high temperatures. Recently, we demonstrated that 
macroscopic stability features of a protein can be predicted by 
characterizing the mechanical rigidity of a protein structure at atomic 
resolution during a thermal unfolding simulation. Furthermore, we were able
to identify structural features from which a destabilization of the protein 
structure originates upon thermal unfolding (weak spots). At present, 
such knowledge is exploited in collaboration with an industrial partner for 
data-driven protein engineering by pointing to residues that should be 
varied to obtain a protein with higher thermostability. The approach is 
based on rigidity theory and is referred to as constraint network analysis
(CNA) [Eng. Life Sci. 2008, 8, 507-522].

Aims of the project. While the above results provide a link between 
protein structure, mechanical rigidity, and thermostability, no 
relationship between protein structural stability and enzymatic activity 
has been established. Thus, in the present study, the CNA approach shall 
be further developed for analyzing microscopic stability features of 
mesophilic and thermophilic protein homologues, aiming at understanding 
how adaptive mutations maintain the balance between global rigidity 
(important for macroscopic stability) and local flexibility (important 
for activity) within the protein structures. Based on these insights, a 
method shall be developed for suggesting mutations at weak spots that 
lead to increased thermostability without compromising enzyme activity. 
Initially, the method shall be developed and validated on citrate synthase
as a model system, for which crystal structures from different organisms 
are available that span a temperature range from 30 to 100C. 
Subsequently, the method shall be applied to Lip A, a lipase from 
B. subtilis, in a prospective manner. Experimental work to validate the 
predictions will be performed in the group of Prof. K.-E. Jaeger 
(Research center Julich).

Ideal candidates would have a strong background in bioinformatics, 
biophysics, biochemistry, structural biology or related disciplines. 
Experience/interest in computational biology, molecular biology, 
enzymology as well as programming skills (C, Perl, Python), familiarity 
with the UNIX/Linux operating system, and an interest in developing new 
methodologies are highly desirable.

Detailed information about living and studying in Duesseldorf is provided 
here: http://www.uni-duesseldorf.de/home/Fakultaeten/math_nat/Graduiertenkollegs/biostruct/Application/duesseldorf

For questions related to the scientific aspect of the project, contact 
Holger Gohlke by email to gohlke===uni-duesseldorf.de . 

For application instructions and an application form, refer to 
http://www.gc.bci.tu-dortmund.de/en/vacancies/24 . 
Please note that the application deadline is January 15th, 2010.