Homology Modeling and Molecular Dynamics Simulation Studies of the human resistin protein

Abstract

Resistin is a member of a secretory protein family, known as resistin-like molecules (RELMs) which were exclusively found in mammalian genomes. Though human resistin molecule has high sequence similarity with mouse, its structural and physiological roles differ considerably from mouse and the structural basis of this drastic functional diffrences are unknown The general objectives of our work are to address these issues and to progress towards a better understanding of the structural basis of resistin biology. Our primary focus is (i) to understand the similarities and differences between human and mouse resistin with respect to their structures and (ii) to infer, using computational approaches, putative functionally important residues. For that purpose we have applied known homology modelling approaches to build a comprehensive 3D model for human resistin using mouse crystallographic data as template. We further assessed the structural properties of this 3D model using molecular dynamics techniques. We importantly compared the properties of both mouse and human resistin structures. The structural status of conserved and non-conserved residues between mouse and human resistin were further investigated with particular emphasis on those residues involved in inter-chain contacts and those exposed on the surface. By identifying the few important residues from the above analysis, we further studied and compared the dynamic properties which provide important insights into structural and functional properties of resistin. Our work suggests that there are considerable differences in interchan interactions and contact surface area between human and mouse structures. Our work also suggests that considerable differences in N-terminal helical orientation in the human model.