SEMINAR @ SISSA, SBP, dr. F. Marinelli and dr. V. Leone

[Barbara Corzani]

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STATISTICAL AND BIOLOGICAL PHYSICS SEMINARS
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 Following easy slope paths on a free energy surface



Fabrizio Marinelli, MPI Mainz, Thursday 23, 14:30, room 132



A new method for the automatic exploration and computation of multidimensional free energy landscapes is presented. It relies on concepts derived both from metadynamics and minimum-mode following methods. Like metadynamics the approach uses a certain number of collective variables that are thought to be relevant for the process under investigation and then the exploration of this space is boosted by introducing a history dependent potential that enhance on time the exploration of not visited configurations. Inspired by minimum-mode following methods, the functional form of the bias potential is chosen in order to allow the system escaping a local free energy minimum following the direction of slow motions. This allows using a larger number of collective variables compared to methods that, like metadynamics, are not based on a specific direction of the biasing force. The new technique  is first tested on Ala-Pro  and  Ace-Ala3-Nme peptides, then it is applied to the ab-initio folding  of Trp-cage and Advillin c-terminal headpiece in explicit solvent. For both proteins, starting the simulation from completely unfolded conformations, the method allows to visit a wide range of conformations, including nearly native ones, within a few hundreds of ns. In the case of the Trp-cage, multiple independent simulation runs were also performed to  achieve  a detailed  classification of different possible folding pathways. Based on these results, the new methodology successfully explores the relevant configurations of a multidimensional free energy landscape allowing to predict the main pathways pertaining to complex transitions like the folding of small proteins.

Ion specificity and transport mechanism of the membrane motor of ATP synthase



Vanessa Leone, MPI Mainz, Monday 20, 14:30, room 132



ATPases are membrane-associated proteins that are able to couple ATP synthesis/hydrolysis to proton or sodium flow down or against their electrochemical gradients. The mechanism of these enzymes involves two opposing rotary motors, known as F1 and Fo in the F-type subfamily, which are physically connected by central and lateral stalks. F1 is where ATP is synthesized or hydrolyzed, by a mechanism that is reasonably understood. By contrast, much less is known about the membrane Fo complex, both in regard to its structure and the ion-transport rotary mechanism.  In a close interplay between traditional biochemical approaches and computational techniques we are studying features of the Fo complex (or its equivalent) that have important mechanistic and functional implications. Here I will introduce two of these studies: one is the structural basis for the ion specificity of membrane rotors; second is the structure of the interface where ion binding and release take place, formed by the so-called c-ring and the subunit-a.  In the first study, we built an assembly of a particular archaeal rotor by homology modelling and, subsequently, we compute the free energy of selectivity (Na+vs. H+) by atomistic simulations. The Na+ vs H+ selectivity obtained explains the unique behaviour of this ATPase at different pH and Na+ concentrations. In the second study we derive, upon existing biochemical data, plausible structural models through Rosetta ab-initio folding and docking algorithms. Based on these models, we speculate on the characteristics of the proton pathway across the membrane. 

 

 

 

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Barbara Corzani - FA and SBP Secretariat
SISSA - Via Bonomea 265, 34136 Trieste
Santorio A Building, fourth floor, room 402
Tel: 0403787424
Fax: 0403787466
E-mail:  <mailto:corzani at sissa.it> corzani at sissa.it
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