1 research outputs found
Structural Dynamics of the Precatalytic State of Human Cytochrome c upon T28C, G34C, and A50C Mutations: A Molecular Dynamics Simulation Perspective
The native structure of cytochrome c (cytc) contains
hexacoordinate heme iron with His18 and Met80 residues ligated at
the axial sites. Mutations of cytc at Ω-loops have been investigated
in modulating the peroxidase activity and, hence, related to the initiation
of the apoptotic pathway. Our previous experimental data reported
on the peroxidase activity of the cysteine-directed mutants at different
parts of the Ω-loop of human cytc (hCytc), that is, T28C, G34C,
and A50C. In this work, we performed 1 μs molecular dynamics
(MD) simulations to elucidate the detailed structural and dynamic
changes upon these mutations, particularly at the proximal Ω-loop.
The structures of hCytc were modeled in the hexacoordinated form,
which was referred to as the “precatalytic state”. The
results showed that the structural features of the G34C mutant were
more distinctive than those of other mutants. G34C mutation caused
local destabilization and flexibility at the proximal Ω-loop
(residues 12–28) and an extended distance between this Ω-loop
region and heme iron. Besides, analysis of the orientation of the
Arg38 side chain of the G34C mutant revealed the Arg38 conformer facing
away from the heme iron. The obtained MD results also suggested structural
diversity of the precatalytic states for the three hCytc mutants,
specifically the effect of G34C mutation on the flexibility of the
proximal Ω-loops. Therefore, our MD simulations combined with
previous experimental data provide detailed insights into the structural
basis of hCytc that could contribute to its pro-apoptotic function