Project : Structural Analysis of Proteins with Disease Causing mutations in them

	The activity of an enzymatic protein depends on the spatial positioning of the substituent domains harbouring the key active site residues. Disruption of any of the structures forming part of these domains would lead to a change in the conformation at the active site region, thereby affecting the function. The conformational flexibility of the residues near the active or substrate binding site is also important for proper docking of the substrate into the active site. Residue mutations occurring in proteins may have either deleterious or neutral effect on the functionality of the protein depending on the extent to which they alter the structure. The aim of this project is to simulate the structural changes that are brought out by disease mutations in an attempt to characterise structural characteristics of proteins with disease mutations. As a case study, we have considered Human CYP1b1 protein which is believed to play an important role in the development of trabecular meshwork in the eyes. Certain mutations in CYP1b1 have been discovered in patients suffering from primary congenital glaucoma (PCG). We modeled these mutations into the CYP1b1 structure and subjected the 'wild-type' and the PCG mutant structures to long time scale molecular dynamics (MD) simulations. 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 (Achary et al, 2006). Further to get a complete description of the dynamic properties from the MD simulation, we are carrying out Essential Dynamics Simulations (in order words principle component analysis) and dynamic cross-correlation maps to yield information about the global correlated motions in the wild type and disease mutants. (Achary and Nagarajaram, Manuscript under preparation). People involved
Sridhar Acharya M Senior Research Fellow
	Publications Research Articles Achary MS, Reddy AB, Chakrabarti S, Panicker SG, Mandal AK, Ahmed N, Balasubramanian D, Hasnain SE, Nagarajaram HA. Disease-causing mutations in proteins: structural analysis of the CYP1B1 mutations causing primary congenital glaucoma in humans. Biophys J. (2006) 91(12), 4329-39 Achary MS and Nagarajaram HA Dynamics-Function Correlation studies on the wild type and PCG-Associated Mutant Forms of Human CYP1b1(Manuscript under preparation) Posters Presented Achary MS, Reddy ABM, Panicker SG, Mandal AK, Balasubramanian D, Hasnain SE and Nagarajaram, H.A.(2005): "Molecular Dynamics studies on Human CYP1B1 with Primary Congenital Glaucoma Associated Mutations." presented at BIOINFOSUMMER, 2005, Canberra, Australia. Achary MS and Nagarajaram, H.A.(2006): "Dynamics-Function correlation studies on the wild type and PCG-Associated Mutant forms of Human CYP1b1." presented at INCOB, 2006 New Delhi.