Improving Internal Peptide Dynamics in the Coarse-Grained MARTINI Model: Application in Amyloid Peptide Aggregation

Abstract

The assembly of misfolded protein aggregates into amyloid fibrils is at the heart of the development of neurodegenerative disorders such as Alzheimer's disease and prion diseases [1, 2]. Despite its significance, the driving forces behind the aggregation of peptides and protein misfolding are not well understood. In order to gain molecular insight into the aggregation of amyloid peptides, we carried out computer simulations using the coarse-grained (CG) model. The application of CG models to peptide aggregation allow for a direct examination of the process in silico since they offer the possibility of investigating complex biological processes over relatively long periods of time and length scales at a reduced level of detail. The recently developed MARTINI coarse-grained model [3], in particular, reproduces a wide range of lipid properties as well as lipid-protein interactions for rigid proteins. Protein folding and aggregation however often involve significant transitions between secondary structures and hence requires that the proteins be flexible during the simulations. We present recent advances on our extension of the MARTINI model to more accurately describe the internal flexibility of peptides by introducing in the energy function a term that accounts for the dihedral potentials on the peptide backbone. The improved model is applied to the self-assembly of beta-sheet forming peptides as a simple model system for aggregation. We characterize the conformation of peptides and follow their self-aggregation in water and at the water-octane interface. Peptide-peptide interactions as well as the interactions of the aggregates with their surroundings are examined. 1. Lührs, T. et al., Proc. Natl. Acad. Sci. USA, 102, 17342–17347 (2005) 2. Nelson, R. et al., Nature, 435, 773–778 (2005) 3. Monticelli, L. et al., J. Chem. Theory and Comput., 4, 819–834 (2008)