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Prof. Tamas from Hungarian Academy of Sciences visited our lab!

Theoretical and experimental studies of  self-assembling protein and lipid systems

Tamás Beke-Somfai


Research Centre for Natural Sciences, Hungarian Academy of Sciences

1117


Budapest, Magyar tudósok krt.2


Summary

In a wide range of biological activities, from cell locomotion to membrane transport, Nature

deploys numerous sophisticated molecular machines which have become highly


optimized for performance and controllability. These assemblies are often


composed of multiple separate components which gather for various specific


purposes. Rational design and engineering of similarly complex biosystems is a


very exciting field with a potential to dramatically alter future’s medicine or


industrial biochemistry [1, 2]. However, to overcome major challenges in areas


such as design of artificial enzymes, or membrane active designed compounds


mimicking natural ones, the precise understanding of their mechanisms especially


of their key steps is required. Here I will focus on two examples where it is


challenging to gain insight to such mechanistic details.


1. FoF1 ATP synthase is interesting as a model


system: a delicate molecular machine synthesizing or hydrolyzing ATP utilizing


a rotary motor. Isolated F1 performs hydrolysis with a rate very


sensitive to ATP concentration. Experimental and theoretical results show that


at low ATP concentrations ATP is slowly hydrolyzed in the so called tight


binding site, whereas at higher concentrations the binding of further ATP


molecules induce rotation of the central g-subunit thereby


forcing the site to transform via subtle conformational changes into a loose


binding site, in which hydrolysis occurs faster. By a combination of


theoretical approaches we addressed how large macromolecular rearrangements may


manipulate 1?-scale rearrangements in the active site and how the reaction rate


changes as a consequence [3]. Simulations reveal that in response to g-subunit position,


the active site conformation is fine-tuned mainly by small a-subunit changes


[4]. It is hoped that in the future the design of bioinspired complex systems


arrives to the age where fine-tuning and precise control on desired processes


can be achieved


2. In the recent decades, development of resistance by bacteria to


antibiotics makes better understanding of antimicrobial mechanisms increasingly


important. Toxic oligomers of antimicrobial peptides (AMPs) may assemble into


hydrophilic or lipophilic complexes and exert their toxicity in a higher level


aggregate form. However, this mechanism is not understood, greatly hindering


rational development of similar compounds.


In this part of the presentation an overview is given on our recent


studies related to both natural and non-natural peptide oligomer assemblies and


their aggregates when associated with organic small molecules. We have


experienced several interactions resulting in induced conformational changes


for these compounds. Several of the observed secondary structures are rather


different from those regularly obtained for well studied AMPs indicating that


the action mechanism of these compounds may be different when exerting their


toxicity in in vivo conditions in presence of a complex multicomponent


environment. Also, I aim to describe new methods available in our laboratory


which are capable to address membrane systems in solution phase. In particular


I will focus on polarized light spectroscopy and on Linear Dichroism coupled to


a Couette Flow-cell (Flow-LD). By today, flow-LD can be used to characterize bicellar


systems or induce lipid bilayer fusion to test mechanisms related to cell


fusion or lipid bilayer mixing [5-7]


[1] Senes Curr. Op. Struct. Biol. 2011, 21, 460-466


[2] Jiang et al. Science, 2008, 319, 1387-1391

[3] Beke-Somfai, et al. Proc. Natl. Acad. Sci. USA, 2011, 108, 4828-4833

[4] Beke-Somfai, et al. Proc. Natl. Acad. Sci. USA, 2013, 6, 2117-2122

[5] Nordén et al. (2010), Linear Dichroism and Circular Dichroism. A Textbook on Polarized-Light Spectroscopy.

[6] Kogan et al. Langmuir, 2014, 30, 4875-4878

[7] Rocha et al. Langmuir, 2016, 32, 2841-2846