Structures and Free Energy Landscapes of the A53T Mutant-Type α-Synuclein Protein and Impact of A53T Mutation on the Structures of the Wild-Type α-Synuclein Protein with Dynamics

The A53T genetic missense mutation of the wild type alpha-synuclein (alpha S) protein was initially identified in Greek and Italian families with familial Parkinson's disease. Detailed understanding of the structures and the changes induced in the wild-type aS structure by the A53T mutation, as well as establishing the direct relationships between the rapid conformational changes and free energy landscapes of these intrinsically disordered fibrillogenic proteins, helps to enhance our fundamental knowledge and to gain insights into the pathogenic mechanism of Parkinson's disease. We employed extensive parallel tempering molecular dynamics simulations along with thermodynamic calculations to determine the secondary and tertiary structural properties as well as the conformational free energy surfaces of the wild-type and A53T mutant-type alpha S proteins in an aqueous solution medium using both implicit and explicit water models. The confined aqueous volume effect in the simulations of disordered proteins using an explicit model for water is addressed for a model disordered protein. We also assessed the stabilities of the residual secondary structure component interconversions in alpha S based on free energy calculations at the atomic level with dynamics using our recently developed theoretical strategy. To the best of our knowledge, this study presents the first detailed comparison of the structural properties linked directly to the conformational free energy landscapes of the monomeric wild-type and A53T mutant-type alpha-synuclein proteins in an aqueous solution environment. Results demonstrate that the beta-sheet structure is significantly more altered than the helical structure upon A53T mutation of the monomeric wild-type alpha S protein in aqueous solution. The beta-sheet content close to the mutation site in the N-terminal region is more abundant while the non-amyloid-beta component (NAC) and C-terminal regions show a decrease in beta-sheet abundance upon A53T mutation. Obtained results utilizing our new theoretical strategy show that the residual secondary structure conversion stabilities resulting in a-helix formation are not significantly affected by the mutation. Interestingly, the residual secondary structure conversion stabilities show that secondary structure conversions resulting in beta-sheet formation are influenced by the A53T mutation and the most stable residual transition yielding beta-sheet occurs directly from the coil structure. Long-range interactions detected between the NAC region and the N- or C-terminal regions of the wild-type alpha S disappear upon A53T mutation. The A53T mutant-type alpha S structures are thermodynamically more stable than those of the wild-type alpha S protein structures in aqueous solution. Overall, the higher propensity of the A53T mutant-type alpha S protein to aggregate in comparison to the wild-type alpha S protein is related to the increased beta-sheet formation and lack of strong intramolecular long-range interactions in the N-terminal region in comparison to its wild-type form. The specific residual secondary structure component stabilities reported herein provide information helpful for designing and synthesizing small organic molecules that can block the beta-sheet forming residues, which are reactive toward aggregation.