Rossetti G, Magistrato A, Pastore A, Carloni P

Polyglutamine beta-sheet aggregates are associated with the derangement of Huntington's disease. The effect of cooperativity of the H-bond network formed by both backbone and side chain groups is expected to be important for the structure and energetics of the aggregates. So far, no direct description and/or quantification of the effect is yet available. By performing DFT and hybrid DFT/MM simulations of polyglutamine beta-sheet structures in vacuo and in aqueous solution, we observe that the cooperativity of glutamine side chains affects both the directions perpendicular and parallel to the backbone. This behavior is not usually observed in beta sheets and may provide significant extra-stabilization together with explaining some of the unique properties of polyglutamine aggregation.