Effects of disease causing mutations on the essential motions in proteins.
This study embodies a detailed comparative analysis of the essential motions of the Wild type and the eight different disease mutant forms of the Human CYP1b1. The mutations considered in this study have been implicated in Primary Congenital Glaucoma, an in-born, genetic disorder associated with eye-abnormality. The principal component analysis for Wild type and the Mutants was carried out using the stabilized molecular dynamics trajectories, which ranged from 35 to 45 nanoseconds. Investigations revealed the nature of the collective motions that characterize functionally relevant 'essential motions'. The essential motions in Wild type are characterized by the collective motions of the Substrate Access Channel including the beta-rich domain and the loops in the region of p450-reductase interaction. Comparative analysis of the essential motions of the Wild type and Mutants, especially those involving the functionally important regions indicated distinct differences in their magnitudes as well as the residue-wise distribution. The Mutants in general are associated with higher root mean square fluctuations, and involve some of the relatively intact core regions of the protein, in large collective motions. This study sheds light on the possible effects of disease causing mutations on the large functionally important collective motions in proteins.
Achary
Malkaram S
MS
Centre for DNA Fingerprinting and Diagnostics, Gruhakalpa Complex, Nampally, Hyderabad, India.
Nagarajaram
Hampapathalu A
HA
D000595:Amino Acid Sequence; D001189:Aryl Hydrocarbon Hydroxylases; D065633:Cytochrome P-450 CYP1B1; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000235:genetics*; D005901:Glaucoma / Q000151:congenital* / Q000235:genetics*; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D011487:Protein Conformation; D013816:Thermodynamics
D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1