Computational Biology - Publications

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Browsing Computational Biology - Publications by Author "Achary, Malkaram S."
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    Disease-causing mutations in proteins: Structural analysis of the CYP1b1 mutations causing primary congenital glaucoma in humans
    ( 2006-01-01) Achary, Malkaram S. ; Reddy, Aramati B.M. ; Chakrabarti, Subhabrata ; Panicker, Shirly G. ; Mandal, Anil K. ; Ahmed, Niyaz ; Balasubramanian, Dorairajan ; Hasnain, Seyed E. ; Nagarajaram, Hampapathalu A.
    In this communication, we report an in-depth structure-based analysis of the human CYP1b1 protein carrying disease-causing mutations that are discovered in patients suffering from primary congenital glaucoma (PCG). The "wild-type" and the PCG mutant structures of the human CYP1b1 protein obtained from comparative modeling were subjected to long molecular dynamics simulations with an intention of studying the possible impact of these mutations on the protein structure and hence its function. Analysis of time evolution as well as time averaged values of various structural properties - especially of those of the functionally important regions: the heme binding region, substrate binding region, and substrate access channel - gave some insights into the possible structural characteristics of the disease mutant and the wild-type forms of the protein. In a nutshell, compared to the wild-type the core regions in the mutant structures are associated with subtle but significant changes, and the functionally important regions seem to adopt such structures that are not conducive for the wild-type-like functionality. © 2006 by the Biophysical Society.
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    Effects of disease causing mutations on the essential motions in proteins
    ( 2009-01-01) Achary, Malkaram S. ; Nagarajaram, Hampapathalu A.
    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 CYPlbl. 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 β-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. © 2009 Taylor & Francis Group, LLC.