"Protein misfolding is an intrinsic aspect of normal folding within the complex cellular environment, and its effects are minimized in living systems by the action of a range of protective mechanisms including molecular chaperones and quality control systems. Unfolded and misfolded proteins have a tendency to aggregate to form a variety of species including the highly organized and kinetically stable amyloid fibrils. The latter species represent a generic form of structure resulting from the inherent polymer properties of polypeptide chains, and their formation is associated with a wide range of debilitating human diseases. Amyloid fibrils and their precursors appear to have similar adverse effects on cellular function regardless of the sequence of the component peptide or protein. Our increasing knowledge of the interplay between different forms of protein structure and their generic characteristics provides a platform for rational therapeutic intervention designed to prevent or treat this whole family of diseases.” (C. M. Dobson, in Protein Misfolding, Aggregation, and Conformational, (2006), pp. 21-41
My global interests involve:
Protein misfolding and aggregation:
1. Kinetics and thermodynamics of the aggregation and amyloid formation.
2. Structures of aggregated proteins (including morphology of fibrils).
3. Structure-disease relation.
4. Thermodynamics of amyloid-ligand interactions.
1. Structures of aggregates, especially infective material.
2. Structure-infectivity-disease relation.
Currently I’m focusing on:
1. Thermodynamics of amyloid-ligand interactions.
New potential inhibitors of aggregation and amyloid formation are reported every year. But mechanisms of inhibition are not well-explored. Thus, thermodynamic studies of protein-ligand interactions before aggregation, amyloid-ligand interactions after aggregation and ligand influence to aggregation kinetics, thermodynamics and structure of aggregates are very important. The results of such studies may be useful for evaluation of inhibitors as potential drugs against various amyloidogenic diseases. Better understanding of inhibition mechanism would allow targeted construction of antiamyloidogenic compounds.
2. Amyloid-like nature of prions and prion-like nature of amyloids.
Our current study on the infective mammalian prion structure [Smirnovas et. al., NSMB, 2011
] revealed new constraints. While these constraints argue against currently suggested models of infective mammalian prion structure, there is a good fit for amyloid-like structure. Molecular infectivity of amyloid fibrils in vitro is well known. As well as ability to form different structures of amyloid aggregates acting in a prion-strain-like manner [Dzwolak et. al., Protein Sci., 2004
]. The only missing part was amyloid infectivity in vivo. Currently it also gets addressed [Eisele et. al., Science, 2010
]. All these findings suggest that in future we may be talking about generic nature of protein infectivity. At this point I’m interested in comparing elongation thermodynamics for different amyloid fibrils at varying conditions, which may give a better understanding on protein-only infectivity.