Combining simulations and deep mutagenesis to elucidate structural dynamics of monoamine transporters

Abstract

Monoamine transporters initiate the reuptake of neurotransmitters serotonin, dopamine, and norepinephrine from the synaptic cleft, thereby terminating neurotransmission. These transporters are widely targeted for the treatment of various neuropsychiatric disorders as well as drugs of abuse. While structural studies have illuminated the architecture of antidepressant binding among these transporters, the conformational dynamics involved in substrate transport and ion-coupling remains unclear. To investigate the structural dynamics of this class of transporters, we performed molecular dynamics simulations of the human serotonin transporter (SERT) and human dopamine transporter (DAT) and implemented adaptive sampling to efficiently explore the conformational landscape.