ATP synthase is—to use a phrase due to Boyer—”a splendid molecular machine” that plays a central role in cellular bioenergetics, but due to its complex structure and multiple inhibition mechanisms has also recently emerged as an attractive target for the development of novel therapeutics. The goal of the current project is to advance our understanding of the mechanism of action of ATP synthase, with a special emphasis on the possibility of selective inhibition of the microbial forms of the enzyme with small molecules. In particular, we intend to use state-of-the-art molecular simulation techniques to examine the energy conversion mechanism in the catalytic portion of ATP synthase and to identify differences in this mechanism that could allow for selective inhibition. Additionally, we would like to explore the possibility of extending the antimicrobial spectrum of existing drugs targeting the ion-translocating portion of ATP synthase and to elucidate the mechanism by which these drugs interfere with proton translocation. The proposed research will provide an important insight into the structural determinants of the mechanochemical coupling in a remarkable biological engine and will also contribute to developing innovative antimicrobial strategies.
Preparing, performing and analyzing molecular dynamics simulations aimed at understanding the mechanism of action of F1-ATPase, with a special emphasis on the differences between mammalian and microbial forms of the enzyme. Studies on the effect of Fo inhibitors on the mechanism of proton translocation using free energy simulations and QM/MM ab-initio molecular dynamics. Understanding the structural basis of selective affinity of diaryloquinolines for mycobacterial form of the Fo motor using enhanced-sampling molecular dynamics and molecular docking. Structure-guided optimization of diarylquinoline scaffold towards selective affinity for Gram+ and Gram- forms of the Fo protein using virtual screening through fragment-based lead optimization
1. Candidates have to hold a MSc degree and be eligible to enroll in a PhD program at Gdansk University of Technology in an independent recruitment procedure
2 Candidates are expected to hava a strong background in physics, physical chemistry, applied mathematics, bioinformatics, computer science or related fields, as documented by good grades in quantitatively oriented courses, and commitment to pursue theoretical and numerical research on real-life problems.
3. Experience in applying computational tools to study biological or chemical phenomena will be an advantge.
4. Programming experience (python, C/C++, scripting languages, etc.), preferably in Linux/Unix environment, proficiency in scientific software (MATLAB, Mathematica, computational chemistry and physics tools) and experience in application of numerical methods will be considered strong assets.
5. Fluency in English.
What we offer:
1. PhD scholarship of 2500 zł/month (tax-exempt, in addition to the standard PhD scholarship in Poland of ca. 1500 zł/month),
paid for full 4 years, starting on October 1, 2019; when adjusted for the costs of living in Gdansk, the total salary
is competitive while benefits include health insurance in Poland and EU
2. The project provides opportunities to pursue scientific internships in the renowned Max Planck Institute for
Biophysical Chemistry in Goettingen, as well as at the Leiden University (Netherlands).
3. During the course of the studies, the base salary can be further increased based on criteria of academic excellence;
non-Polish students can also apply for additional scholarships for foreign graduate students.
How to apply:
Detailed informations are available from the project manager Dr. Jacek Czub, to whom all applications should be addressed:
e-mail: [email protected] http://www.chem.pg.edu.pl/kbm
Gdansk University of Technology
Chemistry Building A, room 219A
Narutowicza St 11/12, 80-233 Gdańsk
Please submit your application before September 31 2018 by email including:
1. Motivation letter
3. Academic record of courses and grades (official transcript)
4. Contact details of at least one referee (preferably a supervisor of MSc thesis)
 J. Czub, M. Wieczór, B. Prokopowicz, H. Grubmüller. Mechanochemical Energy Transduction during the Main Rotary Step in the Synthesis Cycle of F1-ATPase. J. Am. Chem. Soc. 2017, 139, 4025–4034.
 J. Czub, H. Grubmüller. Rotation Triggers Nucleotide-Independent Conformational Transition of the Empty β Subunit of F1-ATPase. J. Am. Chem. Soc. 2014, 136, 6960–6968.
 J. Czub, H. Grubmüller. Torsional elasticity and energetics of F1-ATPase. Proc. Natl. Acad. Sci. USA 2011, 108:7408–7414.