Conformational Ensembles from Experimental Data and Computer Simulations

Conformational Ensembles from Experimental Data and Computer Simulations

Poster Abstracts

8-POS Board 8 Conformational Landscape of Dystrophin’s Actin Binding Domain 1 by Molecular Dynamics Simulations Benjamin Horn 1 , Michael Fealey 2 , Anne Hinderliter 1 , David Thomas 2 , Alessandro Cembran 1 . 1 University of Minnesota Duluth, Duluth, MN, USA, 2 University of Minnesota, Minneapolis, MN, USA. The primary role of dystrophin is to stabilize the membrane of muscle cells against the mechanical forces deriving from muscle contraction and relaxation; its absence or mutation lead to various forms of muscular dystrophy. Dystrophin is connected at the protein’s N-terminus to the actin protein through the actin binding domain 1 (ABD1), formed by two calponin-homology (CH) domains connected by a linker. Double electron-electron resonance experiments indicate that the ABD1 domain of dystrophin switches from a compact to an extended conformation upon binding to actin. We hypothesize that hydrophobic interactions are the main driving force promoting the conformational transition toward the compact ensemble in the absence of actin. To test this hypothesis we performed molecular dynamics simulations of the ABD1 domain of dystrophin, of the ABD1 domain of the utrophin homolog, and of dystrophin’s ABD1 mutants. Our results confirmed that disruption of the hydrophobic interactions leads to a destabilization of specific compact conformations, but also showed that the compact ensemble of the protein is resilient to hydrophobic-to-hydrophilic mutations. On the contrary, mutations that affect the overall charge of the two CH domains had a much more significant impact on the equilibrium, and led to a larger shift toward the extended state. Together, these data indicate that electrostatic interactions play an important role in the extended to compact conformational transition, and that the complementarity in hydrophobic interactions characterizes the specific compact conformations that are stabilized.

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