Proteins are biomolecules consisting of one or more amino acids that carry out a vast array of functions within organisms. However, proteins can also be the cause of various diseases when, for example, they aggregate into particular structures.
Characteristic examples of such aggregates are virus capsids, which can lead to many infectious diseases, and fibrils or oligomers, which can lead to neurodegenerative diseases such as the well-known Alzheimer’s and Parkinson’s diseases. Hence, if we would like to prevent or cure diseases caused by such protein aggregates, we need to understand how they self-assemble into these structures and study their properties. Given that these processes occur at molecular scales and depend on the way proteins interact with each other under different conditions (e.g. temperature), our method of choice is molecular-level computer simulation.
This project succeeded in building such models, which can be used by researchers to study protein aggregation phenomena. Two of these models are currently known in the literature as the GoMARTINI and the GEN (Generalised Elastic Network) models and provide us with new capabilities in this research area of biophysics. In particular, by using these novel models in our studies, we were able to describe the self-assembly of small virus capsids with or without the presence of their genome at the molecular level by identifying the conditions that favour the formation of initial and intermediate key structures (transition states) that will eventually lead to well-formed capsids, that is, capsids that have been identified experimentally. Moreover, we were able to study various properties of these capsids, including their mechanical and thermodynamic stability.
Given that our models are suitable for the study of any system consisting of proteins, our methodology was easily applied in the case of fibrils and oligomers of α-synuclein, which are considered responsible for Parkinson’s disease. In this case, we have conducted a series of computer simulation studies that involved the formation and dissociation of different structures (e.g. fibrils or oligomers that are considered particularly toxic) under different thermodynamic (e.g. temperature) and physicochemical conditions (e.g. pH) or the presence of other neurotoxic molecules such as amyloid-β. As in the case of virus capsids, we were able to unravel the key underlying molecular mechanisms that favour the formation/dissociation of aggregates and identify crucial intermediate structures in these processes. Moreover, we were able to characterize the mechanical properties of α-synuclein fibrils and enable the comparison with neurotoxic amyloid fibrils by using our simulation models, which goes beyond the capabilities of any currently existing experimental setup.
Our studies provide new insights in the formation processes and properties of harmful aggregates anticipating that the acquired knowledge will assist experimentalists in the design of relevant treatments for viral and neurodegenerative diseases.
Our studies also have broader implications in the research area of biophysics and drug design due to the nature of our models, which are able to describe the fundamental physics of many key processes in protein systems. Hence, the acquired knowledge is readily applicable to other research areas including the design of biomaterials for industrial applications.
How did you benefit from the POLONEZ fellowship?
The POLONEZ fellowship has been a great opportunity to start my scientific career in Poland, lead my group, share my experience gained in other countries, meet other POLONEZ fellows, expand my cultural background and benefit from a comprehensive skills programme.
Dr Panagiotis (Panos) Theodorakis is Assistant Professor at the Institute of Physics of the Polish Academy of Sciences. He received his Ph.D. from the University of Ioannina (Greece) and carried out postdoctoral research in Germany (Max Planck Institute for Polymer Research), Austria (University of Vienna), and the United Kingdom (Imperial College London). He has also been a Marie Skłodowska-Curie and Max Planck Fellow. His expertise lies within computer simulation in the areas of soft matter, polymer and statistical physics, fluid physics, and biophysics.