45 / 161
Conformational Ensembles from Experimental Data
and Computer Simulations
Poster Abstracts
41
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.