Dynamic features of carboxy cytoglobin distal mutants investigated by molecular dynamics simulations

Area of Science:

• Biochemistry
• Structural Biology
• Computational Biology

Background:

• Cytoglobin (Cgb) is a hemoprotein involved in NO metabolism, fibrosis, and tumorogenesis.
• Key distal residues significantly influence hemoprotein structure and function, but their specific roles in Cgb are not fully understood.
• His(81) (E7) is known to be critical for ligand binding and heme pocket conformation in Cgb.

Purpose of the Study:

• To investigate the impact of distal residues Leu(46) (B10) and His(81) (E7) on the structure and dynamics of carboxy cytoglobin (CgbCO).
• To explore the effects of single (L46F, L46V) and double (L46F/H81Q, L46V/H81Q) mutations on CgbCO.
• To elucidate the mutual effects of B10 and E7 residues on CgbCO's dynamic features and heme pocket stability.

Main Methods:

• Molecular dynamics (MD) simulations were performed on wild-type and mutant CgbCO.
• Analysis focused on loop region fluctuations, internal cavity rearrangements, and heme motion.
• Key residue interactions, distal pocket volume, and cavity occurrence rates were assessed.

Main Results:

• Distal mutations at B10 and E7 positions altered CgbCO's dynamic properties, including loop fluctuations and heme movement.
• Conformational changes were observed, involving distal residues Gln(62) (CD3) and Arg(84) (E10).
• Mutations affected hydrogen bonds between heme propionates and CD3/E10 residues, and influenced heme pocket volume and internal cavities.

Conclusions:

• The distal residues Leu(46) (B10) and His(81) (E7) play crucial roles in stabilizing the Cgb heme pocket.
• Mutations in these residues impact protein conformational rearrangement and dynamic features.
• These findings suggest that B10 and E7 are critical for ligand binding and overall Cgb biological functions.