Computational Modeling Of 3d Structure Of Keratin Intermediate Filament By Satisfaction Of Spatial Restraints

Abstract

Keratin intermediate filaments are the key structural component of epithelia and

form cytoskeletal network. Till date, the molecular mechanism governing the keratin assembly are unknown. To get insight into keratin (and in general intermediate filament (IF)) assembly and function, we need to know their three-dimensional structures at atomic resolution.

To do this, Hybrid Modeling method was used. In Hybrid Modeling, experimental data is used as spatial restraints. Making use of molecular modeling and converting the chemical cross linking data into spatial restraints a near atomic resolution model of the Keratin (K5/K14) intermediate filament has been created. For the first time, filament structures are solved with almost all residues (missing head/tail).

The resulting structures reveals the configuration of lower order structures inside the filament. These models can help explain the mechanism of keratin related

diseases. They can also be exploited to design experiments to manipulate cytoskeletal structure. Models at atomic level of detail are attractive starting point for the rational drug design. The present approach should be applicable to all proteins of IF family.