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Disease-Causing Mutations in Proteins: Structural Analysis of the CYP1b1 Mutations Causing Primary Congenital Glaucoma in Humans

Malkaram S. Achary ^*, Aramati B. M. Reddy , Subhabrata Chakrabarti , Shirly G. Panicker , Anil K. Mandal , Niyaz Ahmed ^*, Dorairajan Balasubramanian , Seyed E. Hasnain   and Hampapathalu A. Nagarajaram ^*

^* Centre for DNA Fingerprinting and Diagnostics, Hyderabad 500076, India; Prof. Brien Holden Eye Research Centre, L. V. Prasad Eye Institute, Hyderabad 500034, India; Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore 560064, India; and University of Hyderabad, Hyderabad 500046, India

Correspondence: Address reprint requests to Hampapathalu A. Nagarajaram, Centre for DNA Fingerprinting and Diagnostics, Nacharam, Hyderabad 500076 India. Tel.: 91-40-27171502; Fax: 91-40-27155610; E-mail: han{at}cdfd.org.in.

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.