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Abstract
<p class="first" id="P1">Computational evaluation of the energetics of substrate binding,
transport, and release
events of neurotransmitter transporters at the molecular level is a challenge, as
the structural transitions of these membrane proteins involve coupled global and local
changes that span time scales of several orders of magnitude, from nanoseconds to
seconds. Here, we provide a quantitative assessment of the energetics of dopamine
(DA) translocation through the human DA transporter (hDAT), using a combination of
molecular modeling, simulation, and analysis tools. DA-binding and -unbinding events,
which generally involve local configurational changes, are evaluated using free-energy
perturbation or adaptive biasing force methods. The global transitions between the
outward-facing state and the inward-facing state, on the other hand, require a dual-boost
accelerated molecular dynamics simulation. We present results on DA-binding/unbinding
energetics under different conditions, as well as the conformational energy landscape
of hDAT in both DA-bound and -unbound states. The study provides a tractable method
of approach for quantitative evaluation of substrate-binding energetics and efficient
estimation of conformational energy landscape, in general.
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