Structures of the E46KMutant-Type α-Synuclein Protein and Impact of E46K Mutationon the Structures of the Wild-Type α-Synuclein Protein

摘要

The E46K genetic missense mutation of the wild-type α-synuclein protein was recently identified in a family of Spanish origin with hereditary Parkinson’s disease. Detailed understanding of the structures of the monomeric E46K mutant-type α-synuclein protein as well as the impact of the E46K missense mutation on the conformations and free energy landscapes of the wild-type α-synuclein are required for gaining insights into the pathogenic mechanism of Parkinson’s disease. In this study, we use extensive parallel tempering molecular dynamics simulations along with thermodynamic calculations to assess the secondary and tertiary structural properties as well as the conformational preferences of the monomeric wild-type and E46K mutant-type α-synuclein proteins in an aqueous solution environment. We also present the residual secondary structure component conversion stabilities with dynamics using a theoretical strategy, which we most recently developed. To the best of our knowledge, this study presents the first detailed comparison of the structural and thermodynamic properties of the wild-type and E46K mutant-type α-synuclein proteins in an aqueous solutionenvironment at the atomic level with dynamics. We find that the E46Kmutation results not only in local but also in long-range changesin the structural properties of the wild-type α-synuclein protein.The mutation site shows a significant decrease in helical contentas well as a large increase in β-sheet structure formation uponE46K mutation. In addition, the β-sheet content of the C-terminalregion increases significantly in the E46K mutant-type αS incomparison to the wild-type αS. Our theoretical strategy developedto assess the thermodynamic preference of secondary structure transitionsindicates that this shift in secondary structure is the result ofa decrease in the thermodynamic preference of turn to helix conversionswhile the coil to β-sheet preference increases for these residues.Long-range intramolecular protein interactions of the C-terminal withthe N-terminal and NAC regions increase upon E46K mutation, resultingin more compact structures for the E46K mutant-type rather than wild-typeαS. However, the E46K mutant-type αS structures are lessstable than the wild-type αS. Overall, our results show thatthe E46K mutant-type αS has a higher propensity to aggregatethan the wild-type αS and that the N-terminal and C-terminalregions are reactive toward fibrillization and aggregation upon E46Kmutation and we explain the associated reasons based on the structuralproperties herein. Small molecules or drugs that can block the specificresidues forming abundant β-sheet structure, which we reporthere, might help to reduce the reactivity of these intrinsically disorderedfibrillogenic proteins toward aggregation and their toxicity.