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During my research career, I have been involved in quite different aspects of protein biophysics. My path has been relatively ecletic, but with a definite trait d'union: understanding proteins as dynamical chamaleontic systems which can populate lots of dramatically different structures.
- 1 Single molecule AFM force spectroscopy
- 2 Single molecule FRET studies of alpha-synuclein oligomerization
- 3 Coarse grained models for protein folding and aggregation
Single molecule AFM force spectroscopy
- Sandal M., Zuccheri G., Samori B.
- Inside the small length and energy scales of the world of the individual biological molecule,
- in "From cells to proteins: Imaging Nature across dimensions", pp.111-137, Springer, 2005
- (DOI: 10.1007/1-4020-3616-7_7)
- Valle F., Sandal M., Samorì B. The interplay between chemistry and mechanics in the transduction of a mechanical signal into a biochemical function
- Physics Of Life Reviews 2007, 4(3)
- (free arXiv preprint:q-bio/0705.2706)
Two generic reviews about the application single molecule force spectroscopy on proteins and the recent insights on mechanochemistry in biology.
Relationship between mechanical and redox switches in angiostatin
- Sandal M., Grandi F., Samorì B.
- Single molecule force spectroscopy discovers mechanochemical switches in biology: the case of the disulfide bond
- Polymer 47 (7): 2571-2579, 2006
- (doi:10.1016/j.polymer.2005.12.084 )
- Grandi F.#, Sandal M.# Guarguaglini G., Capriotti E., Casadio R., Samorì B.
- Hierarchical mechanochemical switches in Angiostatin
- ChemBioChem 2006, 7,1774-1782 (#=shared first)
- (DOI: 10.1002/cbic.200600227)
In my initial research work, planned and started as an undergraduate, I revealed the presence of mechanical unfolding intermediates in the protein angiostatin, and associated to its disulfide redox state regulation by thioredoxin. The study suggested a novel cell signalling pathway that emerges from the integration of disulfide redox switches and cell migration mechanical forces. The work unveiled how out of equilibrium structures induced by mechanical forces could be of functional interest also for proteins not directly involved in muscle mechanics.
Conformational ensembles of amyloidogenic proteins at the single molecule level
- Sandal M.#, Valle F.#, Tessari I., Mammi S., Bergantino E., Musiani F., Brucale M., Bubacco L., Samorì B.
- Conformational Equilibria in Monomeric Alpha-Synuclein at the Single Molecule Level
- PLoS Biology 2008 6(1):e6 (#=shared first)
- (free open access: doi:10.1371/journal.pbio.0060006) (free arXiv preprint: q-bio:0712.1973)
- Brucale M. , Sandal M. , Di Maio S., Rampioni A., Tessari I., Bubacco L., Samorì B.
- Pathogenic Mutations Shift the Equilibria of alpha-Synuclein Single Molecules towards Structured Conformers
- ChemBioChem 2009 Jan 5;10(1):176-83.
- Sorce B., Sabella S., Sandal M., Samorì B., Santino A., Cingolani R., Rinaldi R., Pompa P.P.
- Single-Molecule Mechanical Unfolding of Amyloidogenic beta(2)-Microglobulin: The Force-Spectroscopy Approach.
- ChemPhysChem 2009 Jun 3
- Sandal M. , Brucale M. , Samorì B.
- Monitoring the conformational equilibria of monomeric intrinsically disordered proteins by single molecule force spectroscopy
- in "Instrumental Analysis of Intrinsically Disordered Proteins: Assessing Structure and Conformation" , edited by Uversky and Longhi , pp. 391-432, John Wiley and Sons. , 2009
I moved towards the experimental determination of the conformational ensembles that proteins populate at equilibrium, focusing on proteins prone to aggregation. I reported the first measurements of an intrinsically unstructured protein ( alpha-synuclein ) conformational equilibria by means of single-molecule force spectroscopy. We reported that shifts in the population of one of the conformational basins are linked to the protein aggregation propensity. The approach that I developed has been recognized as a promising methodology to the study of unstructured proteins. The initial results that we obtained have been further validated by the study of naturally occuring pathogenic variants of alpha-synuclein and to the native-like aggregation of beta-2-microglobulin.
Single molecule force spectroscopy data analysis
- Sandal M., Benedetti F., Brucale M., Gomez-Casado A., Samorì B.
- Hooke: an open software platform for force spectroscopy
- Bioinformatics 2009 Jun 1;25(11):1428-30. Epub 2009 Mar 31
- Software website
I independentely conceived and designed and implemented what has become the de facto standard data analysis application of my own research group, one of the first open source tools for single molecule force spectroscopy. The software has a modular structure which allows for easy extension of its capabilities by users. Currently I am extending the software to include automatic clustering of force curves (Pancaldi P. , Samori` B., Sandal M., manuscript in preparation). It is now used by several other research groups and it is under continous development by an international team. This was the first move for my laboratory into development of data analysis tool and techniques, effectively opening a whole new research avenue in my Bologna laboratory which is now being pursued by students and has led to further publications after I left the group.
Single molecule FRET studies of alpha-synuclein oligomerization
- Cremades N., Chen A.Y. , Orte A., Sandal M., Clarke R., Klenerman D. and Dobson C.M.
(manuscript in preparation)
Coarse grained models for protein folding and aggregation
Sandal M. and Vendruscolo M. (current work)
I have developed a version of the tube model for the molecular dynamics package GROMACS to investigate protein aggregation. Current results seem to explain the bewildering oligomerization diversity observed in experimental investigations of early aggregation processes.