Gabriel Martins, PhD Student at the Chemistry for Biological Systems Research Group, BioISI – Ciências ULisboa, is the first author of a new paper, published in the Neuroscience Journal by the ACS Chemical and coordinated by Nuno Galamba, principal investigator at the same group. In this publication, the authors used molecular simulations techniques to understand the action mechanism of two polyphenols at a molecular level and improve drug design strategies to target neurodegenerative diseases, like Parkinson’s disease. Find out more below.
What was the starting point that led to the current research?
Protein aggregation has been implicated in many human diseases, including neurodegenerative diseases such as Parkinson’s disease (PD). In the case of PD, the formation of a-synuclein (a-syn) – a small intrinsically disordered protein abundant in the brain – oligomers (aka amyloids), leads to the loss of nigral dopaminergic neurons, important in the control of multiple brain functions including voluntary movement. In spite of the report of many small molecule drugs that exhibit aggregation inhibitory activity in vitro, treatments that prevent or disrupt the formation of these cytotoxic oligomers remain unavailable. Furthermore, the action mechanism of these drugs, in particular, many polyphenols, is not always understood. Therefore, we decided to investigate, through molecular simulations, one of the possible aggregation inhibition mechanisms of two (poly)phenols, in the aggregation of 11-mer peptide models from an amyloidogenic region of a-syn. In particular, we studied resveratrol (RSV) and gallic acid (GA), both found to inhibit the aggregation of several proteins in vitro, including a-syn.
What is the main finding reported in this paper?
We show that RSV and GA do not inhibit peptide aggregation. Thus, instead a slight stabilization of the dimers is observed. Additionally, and unexpectedly, these compounds induce a re-orientation of the peptides, favoring peptide-peptide interactions at long distances. Thus, our results suggest that, if anything, RSV and GA modulate or delay peptide aggregation through the stabilization of solvent-separated conformations. Additionally, we studied the structural effect of RSV and GA on the full-length protein. We found that these compounds promote more elongated structures of a-syn, although above therapeutically relevant concentrations. Ultimately, our results support the view that the in vitro effect of these compounds is either linked to their non-covalent binding to oligomeric intermediates of α-syn, or most likely, to the formation of covalent bonds of the respective quinones with α-syn.
If you had to explain the main finding to a 5-year-old child, how would you do it?
There are some diseases that occur because some molecules, known as proteins, that exist in our brain, exhibit abnormal behaviors. In particular, these proteins form aggregates inside or outside our brain cells. That can affect, for instance, our memory or our movement, and we start forgetting about things or stop being able to control movement. Thus, we are interested in understanding the source of this abnormal behavior and find a treatment that prevent those proteins from aggregating. We studied how two specific small molecules may inhibit the formation of these aggregates. We found that these molecules do not inhibit the aggregation of some smaller molecules that are part of the protein that aggregates inside some of our brain cells.
Why is it important for the scientific community and for society at large?
Our findings highlight the importance of understanding the action mechanism of drugs at a molecular level, to improve drug design strategies and/or rule out some molecules as promising leads. While molecular simulations have sampling limitations concerning the study of large proteins and aggregates, they can still provide important insight into pivotal driving forces underlying protein aggregation. This study, in particular, contributes to our understanding of the putative action mechanism of drugs that have been widely studied in vitro.
What are the next steps?
In the future we plan to study the full protein, the dimer, and small oligomers of a-syn, using coarse-grained models, in aqueous solutions of selected drugs, to try to gain insight into the relationship between the structural fluctuations and protein aggregation propensity, in the presence of these drugs. The latter studies will be used toward the rational design of potential cyclic peptides and/or small molecules with the ability to perturb the homogeneous nucleation of a-syn.
Discover more about CBS Group here.
Get to know Nuno Galamba’s research here.
Read the full paper here.
Nuno Galamba and Gabriel Martins (from let to right) [photos provided by the researchers]