BIOPHYSICAL THEORY AND MODELING |
Disease Causing Mutations in Proteins: Structural Analysis
of the CYP1b1 Mutations Causing Primary Congenital
Glaucoma in Humans
Malkaram Sridhar Achary 1, Aramati B.M. Reddy 2, Subhabrata Chakrabarti 2, Shirly G Panicker 2, Anil K Mandal 2, Niyaz Ahmed 1, Dorairajan Balasubramanian 2, Seyed E Hasnain 3 and Hampapathalu Adimurthy Nagarajaram 1*
1 Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad, India
2 L.V. Prasad Eye Institute, Hyderabad, India
3 University of Hyderabad, Hyderabad, India
* To whom correspondence should be addressed. E-mail: han{at}cdfd.org.in.
Submitted on March 22, 2006
Revised on May 3, 2006
Accepted on 21 August 2006
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Abstract |
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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 modelling, were subjected to long molecular dynamics (MD) 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 disease mutant and the wild-type forms of the protein. In a nutshell, as compared to the wild-type the core regions in the mutant structures are associated with subtle but significant changes and that the functionally important regions seem to adopt such structures that are not conducive for the wild-type like functionality.
Key Words:
CYP1b1, Comparative modeling, Comparative sequence analysis, Disease causing mutations, Molecular dynamics simulation, PCG
