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\begin{document}

\title{Effect of phosphorylation on the structural dynamics and thermal
stability of human Dopamine Transporter: a simulation study using Normal
Modes, Molecular Dynamics and Markov State Model}



\author[1]{Roberto Quiroz}%
\author[1]{Philot, EA}%
\author[2]{David Perahia}%
\author[1]{ANA LÍGIA SCOTT}%
\affil[1]{Universidade Federal do ABC Centro de Matematica Computacao e Cognicao}%
\affil[2]{Ecole Normale Superieure Paris-Saclay}%


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  \date{May 25, 2024}


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\begin{abstract}
The Human Dopamine Transporter (hDAT) plays an essential role in
modulating the Influx/Efflux of dopamine, and it is involved in the
mechanism of certain neurodegenerative diseases such as Parkinson's
disease. Macromolecules adopt many conformations in solution depending
on their structure and shape, which determine their dynamics and
function. In this context, several studies have reported important
meta-states for Dopamine transport: outward-facing open state (OFo), the
outward-facing closed state (OFc), the holo-occluded state closed
(holo), and the inward-facing open state (IFo). Furthermore,
experimental assays have shown that different phosphorylation conditions
can affect the rate of dopamine absorption. This work presents a
protocol using hybrid simulation methods to study the conformational
dynamics and stability of meta-states of hDAT under different
phosphorylation states. With this protocol, we explored the
conformational space of hDAT, identified the meta-states, and evaluated
the free energy differences and the transition probabilities between
them in each of the phosphorylation cases. We also presented the
conformational changes and correlated them with those described in the
literature. The results suggest that the phosphorylation corresponding
to NP-333, where (all sites
{[}Ser/Thr{]}(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380854/)
from residue 2 to 62 and residue 254 to 613 are phosphorylated, except
residue 333) is the one that would affect dopamine transport the most,
corroborating the experimental results. Furthermore, our results showed
that just single phosphorylation/dephosphorylation could alter intrinsic
protein motions affecting the sampling of one or more meta-states
necessary for dopamine transport. In this sense, the modification of
phosphorylation influences protein movements and conformational
preferences, affecting the stability of meta-states and the transition
between them and, therefore, the transport.%
\end{abstract}%



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