Molecular dynamics simulation of myopathy-related mutant FHL1 in water and analysis of structure stabilization

Mutations in the FHL1 gene can cause X-linked hereditary myopathy, which causes one of the rarest intractable diseases. The age of the disease onset is quite variable from early infancy to adulthood, and the patients show progressive muscle weakness and atrophy. The FHL1 protein is constituted by four and a half LIM domains. Each LIM domain contains two zinc fingers, which contribute to the structural stability of the LIM domain. A change in the cysteine or histidine residues in the 2nd LIM domain (LIM2) is closely associated with the disease severity. Therefore, LIM2 is suggested to have an essential role in maintaining the structure of FHL1. In this study, molecular dynamics simulation was performed on molecular models consisting of LIM1 and LIM2 of wild and mutant FHL1. We calculated the extent of distortion of zinc finger structure and measured the distance between zinc atom and Cα atom of zinc-coordinated residues. Our analysis showed that the correlation between these two quantities is larger in the mutants associated with severe myopathy.Mutations in the FHL1 gene can cause X-linked hereditary myopathy, which causes one of the rarest intractable diseases. The age of the disease onset is quite variable from early infancy to adulthood, and the patients show progressive muscle weakness and atrophy. The FHL1 protein is constituted by four and a half LIM domains. Each LIM domain contains two zinc fingers, which contribute to the structural stability of the LIM domain. A change in the cysteine or histidine residues in the 2nd LIM domain (LIM2) is closely associated with the disease severity. Therefore, LIM2 is suggested to have an essential role in maintaining the structure of FHL1. In this study, molecular dynamics simulation was performed on molecular models consisting of LIM1 and LIM2 of wild and mutant FHL1. We calculated the extent of distortion of zinc finger structure and measured the distance between zinc atom and Cα atom of zinc-coordinated residues. Our analysis showed that the correlation between these two quantities is larger in the...