Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery: Bridging Experiments and Computations - September 10-14, 2014, Istanbul, Turkey

Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery Poster Session II

51-POS Board 4 Molecular Dynamics and X-Ray Crystallography Reveal the Role of the Skip Regions in Human Cardiac Muscle Protein Myosin Elif N. Korkmaz 1,2 , Keenan C. Taylor 3 , Ivan Raymond 3 , Qiang Cui 1,2 . 1 University of Wisconsin, Madison, Madison, WI, USA, 3 University of Wisconsin, Madison, Madison, WI, USA. 2 University of Wisconsin, Madison, Madison, WI, USA, Cardiac and skeletal muscles contain interdigitated thick and thin filaments, which allow muscle contraction through sliding thick filaments past the actin-containing thin filaments. The globular N-terminal domains generate force through ATP hydrolysis and interactions with actin. The C- terminal region forms a long α-helix and dimerizes to form a coiled-coil (CC), which is known as the myosin rod. Mutations in this rod lead to a wide variety of skeletal and cardiac myopathies. Yet, the molecular organization of the myosin rods is still unresolved. Our ultimate goal is to construct a high-resolution model for the thick filament consisting of 1935 amino acids. To tackle this challenge, a ‘divide and conquer’ type of approach has been employed. The rod includes four Skip residues that disrupt the α-helical heptad-repeat pattern typical for the CCs. We have concentrated on understanding the dynamics of these regions, the role of the Skip residues, and the importance of neighboring residues as a first step toward constructing a model for the thick filament from individual myosin rods. Molecular dynamics simulations are carried out for all four skip regions using the X-Ray structures we recently solved and model structures formed via homology modeling. Several relevant mutants are also studied to dissect the role of the specific neighboring residues. Microsecond simulations are carried out via the AMBER-MD package using implicit solvent. Our results suggest that the Skip1, 2 and 3 determine how well the helices are intertwined. They provide flexibility through increasing the CC pitch with conserved nearby sequences ensuring stability, whereas Skip4 adopts a different behavior consistent with its different functionality. We have found that mutations that cause myopathies are generally located near the Skip residues and disrupt flexibility, and the self-assembly.

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