Mapping Cholesterol Interaction Sites on Serotonin Transporter through Coarse-Grained Molecular Dynamics

Mariarosaria Ferraro, Matteo Masetti, Maurizio Recanatini, Andrea Cavalli and Giovanni Bottegoni

PLOS ONE, 2016, vol. 11, issue 12, 1-24

Abstract: Serotonin transporter (SERT) modulates serotonergic signaling via re-uptake of serotonin in pre-synaptic cells. The inclusion in cholesterol-enriched membrane domains is crucial for SERT activity, suggesting a cross-talk between the protein and the sterol. Here, we develop a protocol to identify potential cholesterol interaction sites coupling statistical analysis to multi-microsecond coarse-grained molecular dynamics simulations of SERT in a previously validated raft-like membrane model. Six putative sites were found, including a putative CRAC motif on TM4 and a CARC motif on TM10. Among them, four hot-spots near regions related to ion binding, transport, and inhibition were detected. Our results encourage prospective studies to unravel mechanistic features of the transporter and related drug discovery implications.

Date: 2016
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pone00:0166196

DOI: 10.1371/journal.pone.0166196

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