(653d) Effect of Co-Solutes On the Thermodynamics of the Aggregation of Peptides

Protein aggregation is responsible for several neuro-degenerative disorders including Alzheimer's disease, Parkinson's diseases etc. Therapeutic protein solutions also degrade mainly due to aggregation, which not only makes it difficult to store them at high concentrations for long periods of time but also reduces their biological activity. In order to counter aggregation, there have been efforts on various levels, which include substitution and chemical modification of protein, or controlling the protein environment using co-solutes. The exact mechanism by which these co-solutes inhibit aggregation is not clear. Selection of additives is therefore done using a heuristic, experimental screening procedure. In order to predict the effect of co-solutes on the free energy of protein aggregation and to elucidate the mechanism of their effect, a computational study is performed to calculate the free energy of association of small peptides with and without co-solutes. The process of aggregate formation is a complex process potentially involving a large number of order parameters. The key order parameters are identified using the MD trajectories between the initial and the final states of the process. These trajectories are generated by heating the system at 1000 K while applying restraints on the fibril. The initial trajectories are also generated using the Temperature accelerated molecular dynamics (TAMD) technique. These trajectories serve as the initial trajectory for the string method in collective variables, which is used to obtain the minimum free energy pathways.