(597a) Estimating the Free Energy of the Association of Amyloid Fibril Forming Peptides

In order to computationally estimate the free energy of association between proteins, association of two proteins in solution have to simulated. However, the required computational time for such a system would be huge. Therefore, association of small amyloid peptides is used as a model system to identify the pathways for their association. These peptides are involved in the contact between the associating proteins and form aggregates which are similar to the protein aggregates. The mechanism of addition of a soluble unstructured monomer to a preformed ordered amyloid fibril is a complex process. On the basis of the kinetics of monomer disassociation of Aβ(1-40) from the amy- loid fibril, it has been suggested that deposition is a multistep process involving a rapid reversible association of the unstructured monomer to the fibril surface (docking) followed by a slower conformational rearrangement leading to the incorporation onto the underlying fibril lattice (locking). Several computational studies have reported many aspects of the dock-lock mechanism for amyloid formation. Similarly, there are various recent studies which have investigated the thermodynamics of this process. However, these studies are limited in accuracy and detail. We have used technqiues such as Temperate accelerated MD, String method in collective variables, and Voronoi-Tesselated Milestoning to obtain the free energy of the peptide association. The advantage of using string method as compared to other computational techniques is that the computational time does not scale as the number of order parameter. We have also investigated the effect of small molecules on the free energy of peptide association.